Haplotype

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Haplotype 

 

DNA molecule 1 differs from DNA molecule 2 at a single base-pair location (a C/A polymorphism).

A haplotype (haploid genotype) is a group of alleles in an organism that are inherited together from a single parent. However, there are other uses of this term. First, it is used to mean a collection of specific alleles (that is, specific DNA sequences) in a cluster of tightly linked genes on a chromosome that are likely to be inherited together—that is, they are likely to be conserved as a sequence that survives the descent of many generations of reproduction. A second use is to mean a set of linked single-nucleotide polymorphism (SNP) alleles that tend to always occur together (i.e., that are associated statistically). It is thought that identifying these statistical associations and few alleles of a specific haplotype sequence can facilitate identifying all other such polymorphic sites that are nearby on the chromosome. Such information is critical for investigating the genetics of common diseases; which in fact have been investigated in humans by the International HapMap Project. Thirdly, many human genetic testing companies use the term in a third way: to refer to an individual collection of specific mutations within a given genetic segment; (see short tandem repeat mutation).

The term 'haplogroup' refers to the SNP/unique-event polymorphism (UEP) mutations that represent the clade to which a collection of particular human haplotypes belong. (Clade here refers to a set of haplotypes sharing a common ancestor.) A haplogroup is a group of similar haplotypes that share a common ancestor with a single-nucleotide polymorphism mutation. Mitochondrial DNA passes along a maternal lineage that can date back thousands of years.

Haplotype resolution

An organism's genotype may not define its haplotype uniquely. For example, consider a diploid organism and two bi-allelic loci (such as SNPs) on the same chromosome. Assume the first locus has alleles A or T and the second locus G or C. Both loci, then, have three possible genotypes: (AA, AT, and TT) and (GG, GC, and CC), respectively. For a given individual, there are nine possible configurations (haplotypes) at these two loci (shown in the Punnett square below). For individuals who are homozygous at one or both loci, the haplotypes are unambiguous - meaning that there is not any differentiation of haplotype T1T2 vs haplotype T2T1; where T1 and T2 are labeled to show that they are the same locus, but labeled as such to show it doesn't matter which order you consider them in, the end result is two T loci. For individuals heterozygous at both loci, the gametic phase is ambiguous - in these cases, you don't know which haplotype you have, e.g., TA vs AT.

	AA	AT	TT
GG	AG AG	AG TG	TG TG
GC	AG AC	AG TC or AC TG	TG TC
CC	AC AC	AC TC	TC TC

The only unequivocal method of resolving phase ambiguity is by sequencing. However, it is possible to estimate the probability of a particular haplotype when phase is ambiguous using a sample of individuals.

Given the genotypes for a number of individuals, the haplotypes can be inferred by haplotype resolution or haplotype phasing techniques. These methods work by applying the observation that certain haplotypes are common in certain genomic regions. Therefore, given a set of possible haplotype resolutions, these methods choose those that use fewer different haplotypes overall. The specifics of these methods vary - some are based on combinatorial approaches (e.g., parsimony), whereas others use likelihood functions based on different models and assumptions such as the Hardy-Weinberg principle, the coalescent theory model, or perfect phylogeny. The parameters in these models are then estimated using algorithms such as the expectation-maximization algorithm (EM), Markov chain Monte Carlo (MCMC), or hidden Markov models (HMM).

Microfluidic whole genome haplotyping is a technique for the physical separation of individual chromosomes from a metaphase cell followed by direct resolution of the haplotype for each allele.

Y-DNA haplotypes from genealogical DNA tests

Unlike other chromosomes, Y chromosomes generally do not come in pairs. Every human male (excepting those with XYY syndrome) has only one copy of that chromosome. This means that there is not any chance variation of which copy is inherited, and also (for most of the chromosome) not any shuffling between copies by recombination; so, unlike autosomal haplotypes, there is effectively not any randomisation of the Y-chromosome haplotype between generations. A human male should largely share the same Y chromosome as his father, give or take a few mutations; thus Y chromosomes tend to pass largely intact from father to son, with a small but accumulating number of mutations that can serve to differentiate male lineages. In particular, the Y-DNA represented as the numbered results of a Y-DNA genealogical DNA test should match, except for mutations. 

UEP results (SNP results)

Unique-event polymorphisms (UEPs) such as SNPs represent haplogroups. STRs represent haplotypes. The results that comprise the full Y-DNA haplotype from the Y chromosome DNA test can be divided into two parts: the results for UEPs, sometimes loosely called the SNP results as most UEPs are single-nucleotide polymorphisms, and the results for microsatellite short tandem repeat sequences (Y-STRs).

The UEP results represent the inheritance of events it is believed can be assumed to have happened only once in all human history. These can be used to identify the individual's Y-DNA haplogroup, his place in the "family tree" of the whole of humanity. Different Y-DNA haplogroups identify genetic populations that are often distinctly associated with particular geographic regions; their appearance in more recent populations located in different regions represents the migrations tens of thousands of years ago of the direct patrilineal ancestors of current individuals.

Y-STR haplotypes

Genetic results also include the Y-STR haplotype, the set of results from the Y-STR markers tested.

Unlike the UEPs, the Y-STRs mutate much more easily, which allows them to be used to distinguish recent genealogy. But it also means that, rather than the population of descendants of a genetic event all sharing the same result, the Y-STR haplotypes are likely to have spread apart, to form a cluster of more or less similar results. Typically, this cluster will have a definite most probable center, the modal haplotype (presumably similar to the haplotype of the original founding event), and also a haplotype diversity — the degree to which it has become spread out. The further in the past the defining event occurred, and the more that subsequent population growth occurred early, the greater the haplotype diversity will be for a particular number of descendants. However, if the haplotype diversity is smaller for a particular number of descendants, this may indicate a more recent common ancestor, or a recent population expansion.

It is important to note that, unlike for UEPs, two individuals with a similar Y-STR haplotype may not necessarily share a similar ancestry. Y-STR events are not unique. Instead, the clusters of Y-STR haplotype results inherited from different events and different histories tend to overlap.

In most cases, it is a long time since the haplogroups' defining events, so typically the cluster of Y-STR haplotype results associated with descendants of that event has become rather broad. These results will tend to significantly overlap the (similarly broad) clusters of Y-STR haplotypes associated with other haplogroups. This makes it impossible for researchers to predict with absolute certainty to which Y-DNA haplogroup a Y-STR haplotype would point. If the UEPs are not tested, the Y-STRs may be used only to predict probabilities for haplogroup ancestry, but not certainties.

A similar scenario exists in trying to evaluate whether shared surnames indicate shared genetic ancestry. A cluster of similar Y-STR haplotypes may indicate a shared common ancestor, with an identifiable modal haplotype, but only if the cluster is sufficiently distinct from what may have happened by chance from different individuals who historically adopted the same name independently. Many names were adopted from common occupations, for instance, or were associated with habitation of particular sites. More extensive haplotype typing is needed to establish genetic genealogy. Commercial DNA-testing companies now offer their customers testing of more numerous sets of markers to improve definition of their genetic ancestry. The number of sets of markers tested has increased from 12 during the early years to 111 more recently.

Establishing plausible relatedness between different surnames data-mined from a database is significantly more difficult. The researcher must establish that the very nearest member of the population in question, chosen purposely from the population for that reason, would be unlikely to match by accident. This is more than establishing that a randomly selected member of the population is unlikely to have such a close match by accident. Because of the difficulty, establishing relatedness between different surnames as in such a scenario is likely to be impossible, except in special cases where there is specific information to drastically limit the size of the population of candidates under consideration. 

Diversity

Haplotype diversity is a measure of the uniqueness of a particular haplotype in a given population. The haplotype diversity (H) is computed as:

${\displaystyle H={\frac {N}{N-1}}(1-\sum _{i}x_{i}^{2})}$
 

where ${\displaystyle x_{i}}$ is the (relative) haplotype frequency of each haplotype in the sample and ${\displaystyle N}$ is the sample size. Haplotype diversity is given for each sample.

Homologous chromosome

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Homologous_chromosome

As this karyotype displays, a diploid human cell contains 22 pairs of homologous chromosomes and 2 sex chromosomes. The cell has two sets of each chromosome; one of the pair is derived from the mother and the other from the father. The maternal and paternal chromosomes in a homologous pair have the same genes at the same locus, but possibly different alleles.

A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points along each chromosome which enable a pair of chromosomes to align correctly with each other before separating during meiosis. This is the basis for Mendelian inheritance which characterizes inheritance patterns of genetic material from an organism to its offspring parent developmental cell at the given time and area.

Overview

Chromosomes are linear arrangements of condensed deoxyribonucleic acid (DNA) and histone proteins, which form a complex called chromatin. Homologous chromosomes are made up of chromosome pairs of approximately the same length, centromere position, and staining pattern, for genes with the same corresponding loci. One homologous chromosome is inherited from the organism's mother; the other is inherited from the organism's father. After mitosis occurs within the daughter cells, they have the correct number of genes which are a mix of the two parents' genes. In diploid (2n) organisms, the genome is composed of one set of each homologous chromosome pair, as compared to tetraploid organisms which may have two sets of each homologous chromosome pair. The alleles on the homologous chromosomes may be different, resulting in different phenotypes of the same genes. This mixing of maternal and paternal traits is enhanced by crossing over during meiosis, wherein lengths of chromosomal arms and the DNA they contain within a homologous chromosome pair are exchanged with one another.

History

Early in the 1900s William Bateson and Reginald Punnett were studying genetic inheritance and they noted that some combinations of alleles appeared more frequently than others. That data and information was further explored by Thomas Morgan. Using test cross experiments, he revealed that, for a single parent, the alleles of genes near to one another along the length of the chromosome move together. Using this logic he concluded that the two genes he was studying were located on homologous chromosomes. Later on during the 1930s Harriet Creighton and Barbara McClintock were studying meiosis in corn cells and examining gene loci on corn chromosomes. Creighton and McClintock discovered that the new allele combinations present in the offspring and the event of crossing over were directly related. This proved interchromosomal genetic recombination.

Structure

Homologous chromosomes are chromosomes which contain the same genes in the same order along their chromosomal arms. There are two main properties of homologous chromosomes: the length of chromosomal arms and the placement of the centromere. 

The actual length of the arm, in accordance with the gene locations, is critically important for proper alignment. Centromere placement can be characterized by four main arrangements, consisting of being either metacentric, submetacentric, acrocentric, or telocentric. Both of these properties are the main factors for creating structural homology between chromosomes. Therefore, when two chromosomes of the exact structure exist, they are able to pair together to form homologous chromosomes.

Since homologous chromosomes are not identical and do not originate from the same organism, they are different from sister chromatids. Sister chromatids result after DNA replication has occurred, and thus are identical, side-by-side duplicates of each other.

In humans

Humans have a total of 46 chromosomes, but there are only 22 pairs of homologous autosomal chromosomes. The additional 23rd pair is the sex chromosomes, X and Y. If this pair is made up of an X and Y chromosome, then the pair of chromosomes is not homologous because their size and gene content differ greatly. The 22 pairs of homologous chromosomes contain the same genes but code for different traits in their allelic forms since one was inherited from the mother and one from the father. So humans have two homologous chromosome sets in each cell, meaning humans are diploid organisms.

Functions

Homologous chromosomes are important in the processes of meiosis and mitosis. They allow for the recombination and random segregation of genetic material from the mother and father into new cells.

In meiosis

During the process of meiosis, homologous chromosomes can recombine and produce new combinations of genes in the daughter cells.

 

Sorting of homologous chromosomes during meiosis.

Meiosis is a round of two cell divisions that results in four haploid daughter cells that each contain half the number of chromosomes as the parent cell. It reduces the chromosome number in a germ cell by half by first separating the homologous chromosomes in meiosis I and then the sister chromatids in meiosis II. The process of meiosis I is generally longer than meiosis II because it takes more time for the chromatin to replicate and for the homologous chromosomes to be properly oriented and segregated by the processes of pairing and synapsis in meiosis I. During meiosis, genetic recombination (by random segregation) and crossing over produces daughter cells that each contain different combinations of maternally and paternally coded genes. This recombination of genes allows for the introduction of new allele pairings and genetic variation. Genetic variation among organisms helps make a population more stable by providing a wider range of genetic traits for natural selection to act on.

Prophase I

In prophase I of meiosis I, each chromosome is aligned with its homologous partner and pairs completely. In prophase I, the DNA has already undergone replication so each chromosome consists of two identical chromatids connected by a common centromere. During the zygotene stage of prophase I, the homologous chromosomes pair up with each other. This pairing occurs by a synapsis process where the synaptonemal complex - a protein scaffold - is assembled and joins the homologous chromosomes along their lengths. Cohesin crosslinking occurs between the homologous chromosomes and helps them resist being pulled apart until anaphase. Genetic crossing-over, a type of recombination, occurs during the pachytene stage of prophase I. In addition, another type of recombination referred to as synthesis-dependent strand annealing (SDSA) frequently occurs. SDSA recombination involves information exchange between paired homologous chromatids, but not physical exchange. SDSA recombination does not cause crossing-over. 

In the process of crossing-over, genes are exchanged by the breaking and union of homologous portions of the chromosomes’ lengths. Structures called chiasmata are the site of the exchange. Chiasmata physically link the homologous chromosomes once crossing over occurs and throughout the process of chromosomal segregation during meiosis. Both the non-crossover and crossover types of recombination function as processes for repairing DNA damage, particularly double-strand breaks. At the diplotene stage of prophase I the synaptonemal complex disassembles before which will allow the homologous chromosomes to separate, while the sister chromatids stay associated by their centromeres.

Metaphase I

In metaphase I of meiosis I, the pairs of homologous chromosomes, also known as bivalents or tetrads, line up in a random order along the metaphase plate. The random orientation is another way for cells to introduce genetic variation. Meiotic spindles emanating from opposite spindle poles attach to each of the homologs (each pair of sister chromatids) at the kinetochore.

Anaphase I

In anaphase I of meiosis I the homologous chromosomes are pulled apart from each other. The homologs are cleaved by the enzyme separase to release the cohesin that held the homologous chromosome arms together. This allows the chiasmata to release and the homologs to move to opposite poles of the cell. The homologous chromosomes are now randomly segregated into two daughter cells that will undergo meiosis II to produce four haploid daughter germ cells.

Meiosis II

After the tetrads of homologous chromosomes are separated in meiosis I, the sister chromatids from each pair are separated. The two haploid(because the chromosome no. has reduced to half. Earlier two sets of chromosomes were present, but now each set exists in two different daughter cells that have arisen from the single diploid parent cell by meiosis I) daughter cells resulting from meiosis I undergo another cell division in meiosis II but without another round of chromosomal replication. The sister chromatids in the two daughter cells are pulled apart during anaphase II by nuclear spindle fibers, resulting in four haploid daughter cells.

In mitosis

Homologous chromosomes do not function the same in mitosis as they do in meiosis. Prior to every single mitotic division a cell undergoes, the chromosomes in the parent cell replicate themselves. The homologous chromosomes within the cell will ordinarily not pair up and undergo genetic recombination with each other. Instead, the replicants, or sister chromatids, will line up along the metaphase plate and then separate in the same way as meiosis II - by being pulled apart at their centromeres by nuclear mitotic spindles. If any crossing over does occur between sister chromatids during mitosis, it does not produce any new recombinant genotypes.

In somatic cells

Homologous pairing in most contexts will refer to germline cells, however also takes place in somatic cells. For example, in humans, somatic cells have very tightly regulated homologous pairing (separated into chromosomal territories, and pairing at specific loci under control of developmental signalling). Other species however (notably Drosophila) exhibit homologous pairing much more frequently. Various functions of homologous pairing in somatic cells have been elucidated through high-throughput screens in the early 21st century. 

Problems

1. Meiosis I 2. Meiosis II 3. Fertilization 4. Zygote Nondisjunction is when chromosomes fail to separate normally resulting in a gain or loss of chromosomes. In the left image the blue arrow indicates nondisjunction taking place during meiosis II. In the right image the green arrow is indicating nondisjunction taking place during meiosis I.

 

There are severe repercussions when chromosomes do not segregate properly. Faulty segregation can lead to fertility problems, embryo death, birth defects, and cancer. Though the mechanisms for pairing and adhering homologous chromosomes vary among organisms, proper functioning of those mechanisms is imperative in order for the final genetic material to be sorted correctly.

Nondisjunction

Proper homologous chromosome separation in meiosis I is crucial for sister chromatid separation in meiosis II. A failure to separate properly is known as nondisjunction. There are two main types of nondisjunction that occur: trisomy and monosomy. Trisomy is caused by the presence of one additional chromosome in the zygote as compared to the normal number, and monosomy is characterized by the presence of one fewer chromosome in the zygote as compared to the normal number. If this uneven division occurs in meiosis I, then none of the daughter cells will have proper chromosomal distribution and severe effects can ensue, including Down’s syndrome. Unequal division can also occur during the second meiotic division. Nondisjunction which occurs at this stage can result in normal daughter cells and deformed cells.

Other uses

Diagram of the general process for double-stranded break repair as well as synthesis-dependent strand annealing.

 

While the main function of homologous chromosomes is their use in nuclear division, they are also used in repairing double-strand breaks of DNA. These double-stranded breaks may occur in replicating DNA and are most often the result of interaction of DNA with naturally occurring damaging molecules such as reactive oxygen species. Homologous chromosomes can repair this damage by aligning themselves with chromosomes of the same genetic sequence. Once the base pairs have been matched and oriented correctly between the two strands, the homologous chromosomes perform a process that is very similar to recombination, or crossing over as seen in meiosis. Part of the intact DNA sequence overlaps with that of the damaged chromosome's sequence. Replication proteins and complexes are then recruited to the site of damage, allowing for repair and proper replication to occur. Through this functioning, double-strand breaks can be repaired and DNA can function normally.

Relevant research

Current and future research on the subject of homologous chromosome is heavily focused on the roles of various proteins during recombination or during DNA repair. In a recently published article by Pezza et al. the protein known as HOP2 is responsible for both homologous chromosome synapsis as well as double-strand break repair via homologous recombination. The deletion of HOP2 in mice has large repercussions in meiosis. Other current studies focus on specific proteins involved in homologous recombination as well. 

There is ongoing research concerning the ability of homologous chromosomes to repair double-strand DNA breaks. Researchers are investigating the possibility of exploiting this capability for regenerative medicine. This medicine could be very prevalent in relation to cancer, as DNA damage is thought to be contributor to carcinogenesis. Manipulating the repair function of homologous chromosomes might allow for bettering a cell’s damage response system. While research has not yet confirmed the effectiveness of such treatment, it may become a useful therapy for cancer.

Synapsis

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Synapsis

Synapsis during Meiosis. The circled area is the part where synapsis occurs, where the two chromatids meet before crossing over

Synapsis (also called syndesis) is the pairing of two homologous chromosomes that occurs during meiosis. It allows matching-up of homologous pairs prior to their segregation, and possible chromosomal crossover between them. Synapsis takes place during prophase I of meiosis. When homologous chromosomes synapse, their ends are first attached to the nuclear envelope. These end-membrane complexes then migrate, assisted by the extranuclear cytoskeleton, until matching ends have been paired. Then the intervening regions of the chromosome are brought together, and may be connected by a protein-RNA complex called the synaptonemal complex. Autosomes undergo synapsis during meiosis, and are held together by a protein complex along the whole length of the chromosomes called the synaptonemal complex. Sex chromosomes also undergo synapsis; however, the synaptonemal protein complex that holds the homologous chromosomes together is only present at one end of each sex chromosome. 

This is not to be confused with mitosis. Mitosis also has prophase, but does not ordinarily do pairing of two homologous chromosomes.

When the non-sister chromatids intertwine, segments of chromatids with similar sequence may break apart and be exchanged in a process known as genetic recombination or "crossing-over". This exchange produces a chiasma, a region that is shaped like an X, where the two chromosomes are physically joined. At least one chiasma per chromosome often appears to be necessary to stabilise bivalents along the metaphase plate during separation. The crossover of genetic material also provides a possible defence against 'chromosome killer' mechanisms, by removing the distinction between 'self' and 'non-self' through which such a mechanism could operate. A further consequence of recombinant synapsis is to increase genetic variability within the offspring. Repeated recombination also has the general effect of allowing genes to move independently of each other through the generations, allowing for the independent concentration of beneficial genes and the purging of the detrimental. 

Following synapsis, a type of recombination referred to as synthesis dependent strand annealing (SDSA) occurs frequently. SDSA recombination involves information exchange between paired non-sister homologous chromatids, but not physical exchange. SDSA recombination does not cause crossing-over. Both the non-crossover and crossover types of recombination function as processes for repairing DNA damage, particularly double-strand breaks.

The central function of synapsis is therefore the identification of homologues by pairing, an essential step for a successful meiosis. The processes of DNA repair and chiasma formation that take place following synapsis have consequences at many levels, from cellular survival through to impacts upon evolution itself. 

Chromosome silencing

In mammals, surveillance mechanisms remove meiotic cells in which synapsis is defective. One such surveillance mechanism is meiotic silencing that involves the transcriptional silencing of genes on asynapsed chromosomes. Any chromosome region, either in males or females, that is asynapsed is subject to meiotic silencing. ATR, BRCA1 and gammaH2AX localize to unsynapsed chromosomes at the pachytene stage of meiosis in human oocytes and this may lead to chromosome silencing. The DNA damage response protein TOPBP1 has also been identified as a crucial factor in meiotic sex chromosome silencing. DNA double-strand breaks appear to be initiation sites for meiotic silencing.

Recombination

In female Drosophila melanogaster fruit flies, meiotic chromosome synapsis occurs in the absence of recombination. Thus synapsis in Drosophila is independent of meiotic recombination, consistent with the view that synapsis is a precondition required for the initiation of meiotic recombination. Meiotic recombination is also unnecessary for homologous chromosome synapsis in the nematode Caenorhabditis elegans.

Chromosome segregation

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Chromosome_segregation

Chromosome segregation is the process in eukaryotes by which two sister chromatids formed as a consequence of DNA replication, or paired homologous chromosomes, separate from each other and migrate to opposite poles of the nucleus. This segregation process occurs during both mitosis and meiosis. Chromosome segregation also occurs in prokaryotes. However, in contrast to eukaryotic chromosome segregation, replication and segregation are not temporally separated. Instead segregation occurs progressively following replication.

Mitotic chromatid segregation

Mitosis divides the chromosomes in a cell nucleus.

During mitosis chromosome segregation occurs routinely as a step in cell division (see mitosis diagram). As indicated in the mitosis diagram, mitosis is preceded by a round of DNA replication, so that each chromosome forms two copies called chromatids. These chromatids separate to opposite poles, a process facilitated by a protein complex referred to as cohesin. Upon proper segregation, a complete set of chromatids ends up in each of two nuclei, and when cell division is completed, each DNA copy previously referred to as a chromatid is now called a chromosome. 

Meiotic chromosome and chromatid segregation

Chromosome segregation occurs at two separate stages during meiosis called anaphase I and anaphase II (see meiosis diagram). In a diploid cell there are two sets of homologous chromosomes of different parental origin (e.g. a paternal and a maternal set). During the phase of meiosis labeled “interphase s” in the meiosis diagram there is a round of DNA replication, so that each of the chromosomes initially present is now composed of two copies called chromatids. These chromosomes (paired chromatids) then pair with the homologous chromosome (also paired chromatids) present in the same nucleus (see prophase I in the meiosis diagram). The process of alignment of paired homologous chromosomes is called synapsis. During synapsis, genetic recombination usually occurs. Some of the recombination events occur by crossing over (involving physical exchange between two chromatids), but most recombination events involve information exchange but not physical exchange between two chromatids. Following recombination, chromosome segregation occurs as indicated by the stages metaphase I and anaphase I in the meiosis diagram. 

Different pairs of chromosomes segregate independently of each other, a process termed “independent assortment of non-homologous chromosomes”. This process results in each gamete usually containing a mixture of chromosomes from both original parents.

Improper chromosome segregation can result in aneuploid gametes having either too few or too many chromosomes. 

The second stage at which segregation occurs during meiosis is prophase II (see meiosis diagram). During this stage, segregation occurs by a process similar to that during mitosis, except that in this case prophase II is not preceded by a round of DNA replication. Thus the two chromatids comprising each chromosome separate into different nuclei, so that each nucleus gets a single set of chromatids (now called chromosomes) and each nucleus becomes included in a haploid gamete (see stages following prophase II in the meiosis diagram). This segregation process is also facilitated by cohesin. Failure of proper segregation during prophase II can also lead to aneuploid gametes. Aneuploid gametes can undergo fertilization to form aneuploid zygotes and hence to serious adverse consequences for progeny. 

Crossovers facilitate segregation, but are not essential

A diagram of the meiotic phases

 

A current model of meiotic recombination, initiated by a double-strand break or gap, followed by pairing with an homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or non-crossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model, illustrated on the left, above. Most recombination events appear to be the SDSA type.

 

Meiotic chromosomal crossover (CO) recombination facilitates the proper segregation of homologous chromosomes. This is because, at the end of meiotic prophase I, CO recombination provides a physical link that holds homologous chromosome pairs together. These linkages are established by chiasmata, which are the cytological manifestations of CO recombination. Together with cohesion linkage between sister chromatids, CO recombination may help ensure the orderly segregation of the paired homologous chromosomes to opposite poles. In support of this, a study of aneuploidy in single spermatozoa by whole genome sequencing found that, on average, human sperm cells with aneuploid autosomes exhibit significantly fewer crossovers than normal cells. After the first chromosome segregation in meiosis I is complete, there is further chromosome segregation during the second equational division of meiosis II. Both proper initial segregation of chromosomes in prophase I and the next chromosome segregation during equational division in meiosis II are required to generate gametes with the correct number of chromosomes.

CO recombinants are produced by a process involving the formation and resolution of Holliday junction intermediates. As indicated in the figure titled "A current model of meiotic recombination", the formation of meiotic crossovers can be initiated by a double-strand break (DSB). The introduction of DSBs in DNA often employs the topoisomerase-like protein SPO11. CO recombination may also be initiated by external sources of DNA damage such as X-irradiation, or internal sources.

There is evidence that CO recombination facilitates meiotic chromosome segregation. Other studies, however, indicate that chiasma, while supportive, are not essential to meiotic chromosome segregation. The budding yeast Saccharomyces cerevisiae is a model organism used for studying meiotic recombination. Mutants of S. cerevisiae defective in CO recombination at the level of Holliday junction resolution were found to efficiently undergo proper chromosome segregation. The pathway that produces the majority of COs in S. cerevisiae, and possibly in mammals, involves a complex of proteins including the MLH1-MLH3 heterodimer (called MutL gamma). MLH1-MLH3 binds preferentially to Holliday junctions. It is an endonuclease that makes single-strand breaks in supercoiled double-stranded DNA, and promotes the formation of CO recombinants. Double mutants deleted for both MLH3 (major pathway) and MMS4 (which is necessary for a minor Holliday junction resolution pathway) showed dramatically reduced crossing over compared to wild-type (6- to 17-fold reduction); however spore viability was reasonably high (62%) and chromosomal disjunction appeared mostly functional.

The MSH4 and MSH5 proteins form a hetero-oligomeric structure (heterodimer) in S. cerevisiae and humans. In S. cerevisiae, MSH4 and MSH5 act specifically to facilitate crossovers between homologous chromosomes during meiosis. The MSH4/MSH5 complex binds and stabilizes double Holliday junctions and promotes their resolution into crossover products. An MSH4 hypomorphic (partially functional) mutant of S. cerevisiae showed a 30% genome-wide reduction in crossover numbers, and a large number of meioses with non-exchange chromosomes. Nevertheless, this mutant gave rise to spore viability patterns suggesting that segregation of non-exchange chromosomes occurred efficiently. Thus it appears that CO recombination facilitates proper chromosome segregation during meiosis in S. cerevisiae, but it is not essential.

The fission yeast Schizosaccharomyces pombe has the ability to segregate homologous chromosomes in the absence of meiotic recombination (achiasmate segregation). This ability depends on the microtubule motor dynein that regulates the movement of chromosomes to the poles of the meiotic spindle.

Chromosome abnormality

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Chromosome_abnormality 

 

The three major single-chromosome mutations: deletion (1), duplication (2) and inversion (3).

 

The two major two-chromosome mutations: insertion (1) and Translocation (2).

 

A chromosomal disorder, anomaly, aberration, or mutation is a missing, extra, or irregular portion of chromosomal DNA. It can be from a typical number of chromosomes or a structural abnormality in one or more chromosomes. Chromosome mutation was formerly used in a strict sense to mean a change in a chromosomal segment, involving more than one gene. The term "karyotype" refers to the full set of chromosomes from an individual; this can be compared to a "normal" karyotype for the species via genetic testing. A chromosome anomaly may be detected or confirmed in this manner. Chromosome anomalies usually occur when there is an error in cell division following meiosis or mitosis. There are many types of chromosome anomalies. They can be organized into two basic groups, numerical and structural anomalies.

Numerical disorders

This is called aneuploidy (an abnormal number of chromosomes), and occurs when an individual either is missing a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (trisomy, tetrasomy, etc.).

An example of trisomy in humans is Down syndrome, which is a developmental disorder caused by an extra copy of chromosome 21; the disorder is therefore also called trisomy 21. Having an extra copy of this chromosome means that individuals have three copies of each of its genes instead of two, making it difficult for cells to properly control how much protein is made. Producing too much or too little protein can have serious consequences. Genes on chromosome 21 that specifically contribute to the various symptoms of Down syndrome are now being identified. The frequency of Trisomy 21 has been determined to be a function of advanced maternal age.

An example of monosomy is Turner syndrome, where the individual is born with only one sex chromosome, an X. 

Sperm aneuploidy

Exposure of males to certain lifestyle, environmental and/or occupational hazards may increase the risk of aneuploid spermatozoa. In particular, risk of aneuploidy is increased by tobacco smoking, and occupational exposure to benzene, insecticides, and perfluorinated compounds. Increased aneuploidy is often associated with increased DNA damage in spermatozoa. 

Structural abnormalities

When the chromosome's structure is altered, this can take several forms:

• Deletions: A portion of the chromosome is missing or deleted. Known disorders in humans include Wolf-Hirschhorn syndrome, which is caused by partial deletion of the short arm of chromosome 4; and Jacobsen syndrome, also called the terminal 11q deletion disorder.
• Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material. Known human disorders include Charcot-Marie-Tooth disease type 1A, which may be caused by duplication of the gene encoding peripheral myelin protein 22 (PMP22) on chromosome 17.
• Translocations: A portion of one chromosome is transferred to another chromosome. There are two main types of translocations:
  • Reciprocal translocation: Segments from two different chromosomes have been exchanged.
  • Robertsonian translocation: An entire chromosome has attached to another at the centromere - in humans these only occur with chromosomes 13, 14, 15, 21, and 22.
• Inversions: A portion of the chromosome has broken off, turned upside down, and reattached, therefore the genetic material is inverted.
• Insertions: A portion of one chromosome has been deleted from its normal place and inserted into another chromosome.
• Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material.
• Isochromosome: Formed by the mirror image copy of a chromosome segment including the centromere.

Chromosome instability syndromes are a group of disorders characterized by chromosomal instability and breakage. They often lead to an increased tendency to develop certain types of malignancies. 

Inheritance

Most chromosome abnormalities occur as an accident in the egg cell or sperm, and therefore the anomaly is present in every cell of the body. Some anomalies, however, can happen after conception, resulting in Mosaicism (where some cells have the anomaly and some do not). Chromosome anomalies can be inherited from a parent or be "de novo". This is why chromosome studies are often performed on parents when a child is found to have an anomaly. If the parents do not possess the abnormality it was not initially inherited; however it may be transmitted to subsequent generations. 

Acquired chromosome abnormalities

Most cancers, if not all, could cause chromosome abnormalities, with either the formation of hybrid genes and fusion proteins, deregulation of genes and overexpression of proteins, or loss of tumor suppressor genes. Furthermore, certain consistent chromosomal abnormalities can turn normal cells into a leukemic cell such as the translocation of a gene, resulting in its inappropriate expression.

DNA damage during spermatogenesis

During the mitotic and meiotic cell divisions of mammalian gametogenesis, DNA repair is effective at removing DNA damages. However, in spermatogenesis the ability to repair DNA damages decreases substantially in the latter part of the process as haploid spermatids undergo major nuclear chromatin remodeling into highly compacted sperm nuclei. As reviewed by Marchetti et al., the last few weeks of sperm development before fertilization are highly susceptible to the accumulation of sperm DNA damage. Such sperm DNA damage can be transmitted unrepaired into the egg where it is subject to removal by the maternal repair machinery. However, errors in maternal DNA repair of sperm DNA damage can result in zygotes with chromosomal structural aberrations.

Melphalan is a bifunctional alkylating agent frequently used in chemotherapy. Meiotic inter-strand DNA damages caused by melphalan can escape paternal repair and cause chromosomal aberrations in the zygote by maternal misrepair. Thus both pre- and post-fertilization DNA repair appear to be important in avoiding chromosome abnormalities and assuring the genome integrity of the conceptus. 

Detection

Depending on the information one wants to obtain, different techniques and samples are needed.

• For the prenatal diagnosis of a foetus, amniocentesis, chorionic villus sampling or circulating foetal cells would be collected and analysed in order to detect possible chromosomal abnormalities.
• For the preimplantational diagnosis of an embryo, a blastocyst biopsy would be performed.
• For a lymphoma or leukemia screening the technique used would be a bone marrow biopsy.

Miscarriage

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Miscarriage

Miscarriage
Other names	Spontaneous abortion, early pregnancy loss
An ultrasound showing a gestational sac containing a yolk sac but no embryo.
Specialty	Obstetrics and gynecology
Symptoms	Vaginal bleeding with or without pain
Complications	Infection, bleeding, sadness, anxiety, guilt
Usual onset	Before 20 weeks of pregnancy
Causes	Chromosomal abnormalities, uterine abnormalities
Risk factors	Being an older parent, previous miscarriage, exposure to tobacco smoke, obesity, diabetes, autoimmune diseases, drug or alcohol use
Diagnostic method	Examination, human chorionic gonadotropin, ultrasound
Differential diagnosis	Ectopic pregnancy, implantation bleeding.
Prevention	Prenatal care
Treatment	Expectant management, misoprostol, vacuum aspiration, emotional support
Frequency	10–50% of pregnancies

Miscarriage, also known as spontaneous abortion and pregnancy loss, is the natural death of an embryo or fetus before it is able to survive independently. Some use the cutoff of 20 weeks of gestation, after which fetal death is known as a stillbirth. The most common symptom of a miscarriage is vaginal bleeding with or without pain. Sadness, anxiety and guilt may occur afterwards. Tissue and clot-like material may leave the uterus and pass through and out of the vagina. When a woman keeps having miscarriages, infertility is present.

Risk factors for miscarriage include an older parent, previous miscarriage, exposure to tobacco smoke, obesity, diabetes, thyroid problems, and drug or alcohol use. About 80% of miscarriages occur in the first 12 weeks of pregnancy (the first trimester). The underlying cause in about half of cases involves chromosomal abnormalities. Diagnosis of a miscarriage may involve checking to see if the cervix is open or closed, testing blood levels of human chorionic gonadotropin (hCG), and an ultrasound. Other conditions that can produce similar symptoms include an ectopic pregnancy and implantation bleeding.

Prevention is occasionally possible with good prenatal care. Avoiding drugs, alcohol, infectious diseases, and radiation may decrease the risk of miscarriage. No specific treatment is usually needed during the first 7 to 14 days. Most miscarriages will complete without additional interventions. Occasionally the medication misoprostol or a procedure such as vacuum aspiration is used to remove the remaining tissue. Women who have a blood type of rhesus negative (Rh negative) may require Rho(D) immune globulin. Pain medication may be beneficial. Emotional support may help with processing the loss.

Miscarriage is the most common complication of early pregnancy. Among women who know they are pregnant, the miscarriage rate is roughly 10% to 20%, while rates among all fertilisation is around 30% to 50%. In those under the age of 35 the risk is about 10% while it is about 45% in those over the age of 40. Risk begins to increase around the age of 30. About 5% of women have two miscarriages in a row. Some recommend not using the term "abortion" in discussions with those experiencing a miscarriage in an effort to decrease distress.

Signs and symptoms

Signs of a miscarriage include vaginal spotting, abdominal pain, cramping, and fluid, blood clots, and tissue passing from the vagina. Bleeding can be a symptom of miscarriage, but many women also have bleeding in early pregnancy and don't miscarry. Bleeding during the first half of pregnancy may be referred to as a threatened miscarriage. Of those who seek treatment for bleeding during pregnancy, about half will miscarry. Miscarriage may be detected during an ultrasound exam, or through serial human chorionic gonadotropin (HCG) testing. 

Risk factors

Miscarriage may occur for many reasons, not all of which can be identified. Risk factors are those things that increase the likelihood of having a miscarriage but don't necessarily cause a miscarriage. Up to 70 conditions, infections, medical procedures, lifestyle factors, occupational exposures, chemical exposure, and shift work are associated with increased risk for miscarriage. Some of these risks include endocrine, genetic, uterine, or hormonal abnormalities, reproductive tract infections, and tissue rejection caused by an autoimmune disorder.

Trimesters

First trimester

Most clinically apparent miscarriages (two-thirds to three-quarters in various studies) occur during the first trimester. About 30% to 40% of all fertilized eggs miscarry, often before the pregnancy is known. The embryo typically dies before the pregnancy is expelled; bleeding into the decidua basalis and tissue necrosis causes uterine contractions to expel the pregnancy. Early miscarriages can be due to a developmental abnormality of the placenta or other embryonic tissues. In some instances an embryo does not form but other tissues do. This has been called a "blighted ovum".

Successful implantation of the zygote into the uterus is most likely 8 to 10 days after conception. If the zygote has not implanted by day 10, implantation becomes increasingly unlikely in subsequent days.

A chemical pregnancy is a pregnancy that was detected by testing but ends in miscarriage before or around the time of the next expected period.

Chromosomal abnormalities are found in more than half of embryos miscarried in the first 13 weeks. Half of embryonic miscarriages (25% of all miscarriages) have an aneuploidy (abnormal number of chromosomes). Common chromosome abnormalities found in miscarriages include an autosomal trisomy (22–32%), monosomy X (5–20%), triploidy (6–8%), tetraploidy (2–4%), or other structural chromosomal abnormalities (2%).^[47] Genetic problems are more likely to occur with older parents; this may account for the higher rates observed in older women.

Luteal phase progesterone deficiency may or may not be a contributing factor to miscarriage.

Second and third trimesters

Second trimester losses may be due to maternal factors such as uterine malformation, growths in the uterus (fibroids), or cervical problems. These conditions also may contribute to premature birth. Unlike first-trimester miscarriages, second-trimester miscarriages are less likely to be caused by a genetic abnormality; chromosomal aberrations are found in a third of cases. Infection during the third trimester can cause a miscarriage.

Age

The age of the pregnant woman is a significant risk factor. Miscarriage rates increase steadily with age, with more substantial increases after age 35. In those under the age of 35 the risk is about 10% while it is about 45% in those over the age of 40. Risk begins to increase around the age of 30. Paternal age is associated with increased risk.

Obesity, eating disorders and caffeine

Not only is obesity associated with miscarriage; it can result in sub-fertility and other adverse pregnancy outcomes. Recurrent miscarriage is also related to obesity. Women with bulimia nervosa and anorexia nervosa may have a greater risk for miscarriage. Nutrient deficiencies have not been found to impact miscarriage rates but hyperemesis gravidarum sometimes precedes a miscarriage.

Caffeine consumption also has been correlated to miscarriage rates, at least at higher levels of intake. However, such higher rates have been found to be statistically significant only in certain circumstances.

Vitamin supplementation has generally not shown to be effective in preventing miscarriage. Chinese traditional medicine has not been found to prevent miscarriage.

Endocrine disorders

Disorders of the thyroid may affect pregnancy outcomes. Related to this, iodine deficiency is strongly associated with an increased risk of miscarriage. The risk of miscarriage is increased in those with poorly controlled insulin-dependent diabetes mellitus. Women with well-controlled diabetes have the same risk of miscarriage as those without diabetes.

Food poisoning

Ingesting food that has been contaminated with listeriosis, toxoplasmosis, and salmonella is associated with an increased risk of miscarriage.

Amniocentesis and chorionic villus sampling

Amniocentesis and chorionic villus sampling (CVS) are procedures conducted to assess the fetus. A sample of amniotic fluid is obtained by the insertion of a needle through the abdomen and into the uterus. Chorionic villus sampling is a similar procedure with a sample of tissue removed rather than fluid. These procedures are not associated with pregnancy loss during the second trimester but they are associated with miscarriages and birth defects in the first trimester. Miscarriage caused by invasive prenatal diagnosis (chorionic villus sampling (CVS) and amniocentesis) is rare (about 1%).

Surgery

The effects of surgery on pregnancy are not well-known including the effects of bariatric surgery. Abdominal and pelvic surgery are not risk factors in miscarriage. Ovarian tumors and cysts that are removed have not been found to increase the risk of miscarriage. The exception to this is the removal of the corpus luteum from the ovary. This can cause fluctuations in the hormones necessary to maintain the pregnancy.

Medications

There is no significant association between antidepressant medication exposure and spontaneous abortion. The risk of miscarriage is not likely decreased by discontinuing SSRIs prior to pregnancy. Some available data suggest that there is a small increased risk of miscarriage for women taking any antidepressant, though this risk becomes less statistically significant when excluding studies of poor quality.

Medicines that increase the risk of miscarriage include:

• retinoids
• nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen
• misoprostol 
• methotrexate
• statins

Immunizations

Immunizations have not been found to cause miscarriage. Live vaccinations, like the MMR vaccine, can theoretically cause damage to the fetus as the live virus can cross the placenta and potentially increase the risk for miscarriage. Therefore, the Center for Disease Control (CDC) recommends against pregnant women receiving live vaccinations. However, there is no clear evidence that has shown live vaccinations to increase the risk for miscarriage or fetal abnormalities.

Some live vaccinations include: MMR, varicella, certain types of the influenza vaccine, and rotavirus.

Treatments for cancer

Ionizing radiation levels given to a woman during cancer treatment cause miscarriage. Exposure can also impact fertility. The use of chemotherapeutic drugs used to treat childhood cancer increases the risk of miscarriage.

Intercurrent diseases

Several intercurrent diseases in pregnancy can potentially increase the risk of miscarriage, including diabetes, polycystic ovary syndrome (PCOS), hypothyroidism, certain infectious diseases, and autoimmune diseases. PCOS may increase the risk of miscarriage. Two studies suggested treatment with the drug metformin significantly lowers the rate of miscarriage in women with PCOS, but the quality of these studies has been questioned. Metformin treatment in pregnancy has not been shown to be safe. In 2007 the Royal College of Obstetricians and Gynaecologists also recommended against use of the drug to prevent miscarriage. Thrombophilias or defects in coagulation and bleeding were once thought to be a risk in miscarriage but have been subsequently questioned. Severe cases of hypothyroidism increase the risk of miscarriage. The effect of milder cases of hypothyroidism on miscarriage rates has not been established. A condition called luteal phase defect (LPD) is a failure of the uterine lining to be fully prepared for pregnancy. This can keep a fertilized egg from implanting or result in miscarriage.

Mycoplasma genitalium infection is associated with increased risk of preterm birth and miscarriage.

Infections can increase the risk of a miscarriage: rubella (German measles), cytomegalovirus, bacterial vaginosis, HIV, chlamydia, gonorrhoea, syphilis, and malaria.

Immune status

Autoimmunity is possible cause of recurrent or late-term miscarriages. In the case of an autoimmune-induced miscarriages the woman's body attacks the growing fetus or prevents normal pregnancy progression. Autoimmune disease may cause genetic abnormalities in embryos which in turn may lead to miscarriage. As an example, Celiac disease increases the risk of miscarriage by an odds ratio of approximately 1.4. A disruption in normal immune function can lead to the formation of antiphospholipid antibody syndrome. This will affect the ability to continue the pregnancy, and if a woman has repeated miscarriages, she can be tested for it. Approximately 15% of recurrent miscarriages are related to immunologic factors. The presence of anti-thyroid autoantibodies is associated with an increased risk with an odds ratio of 3.73 and 95% confidence interval 1.8–7.6.^[82] Having lupus also increases the risk for miscarriage.

Anatomical defects and trauma

Fifteen percent of women who have experienced three or more recurring miscarriages have some anatomical defect that prevents the pregnancy from being carried for the entire term. The structure of the uterus has an effect on the ability to carry a child to term. Anatomical differences are common and can be congenital.

Type of uterine structure	Miscarriage rate associated with defect	References
Bicornate uterus	40–79%	[27][28]
Septate or unicornate	34–88%	[27]
Arcuate	Unknown	[27]
Didelphys	40%	[27]
Fibroids	Unknown	[31]

In some women, cervical incompetence or cervical insufficiency occurs with the inability of the cervix to stay closed during the entire pregnancy. It does not cause first trimester miscarriages. In the second trimester it is associated with an increased risk of miscarriage. It is identified after a premature birth has occurred at about 16–18 weeks into the pregnancy. During the second trimester, major trauma can result in a miscarriage.

Smoking

Tobacco (cigarette) smokers have an increased risk of miscarriage. There is an increased risk regardless of which parent smokes, though the risk is higher when the gestational mother smokes.

Morning sickness

Nausea and vomiting of pregnancy (NVP, or morning sickness) are associated with a decreased risk. Several possible causes have been suggested for morning sickness but there is still no agreement. NVP may represent a defense mechanism which discourages the mother's ingestion of foods that are harmful to the fetus; according to this model, a lower frequency of miscarriage would be an expected consequence of the different food choices made by women experiencing NVP.

Chemicals and occupational exposure

Chemical and occupational exposures may have some effect in pregnancy outcomes. A cause and effect relationship almost can never be established. Those chemicals that are implicated in increasing the risk for miscarriage are DDT, lead, formaldehyde, arsenic, benzene and ethylene oxide. Video display terminals and ultrasound have not been found to have an effect on the rates of miscarriage. In dental offices where nitrous oxide is used with the absence of anesthetic gas scavenging equipment, there is a greater risk of miscarriage. For women who work with cytotoxic antineoplastic chemotherapeutic agents there is a small increased risk of miscarriage. No increased risk for cosmetologists has been found.

Other

Alcohol increases the risk of miscarriage. Cocaine use increases the rate of miscarriage. Some infections have been associated with miscarriage. These include Ureaplasma urealyticum, Mycoplasma hominis, group B streptococci, HIV-1, and syphilis. Infections of Chlamydia trachomatis, Camphylobacter fetus, and Toxoplasma gondii have not been found to be linked to miscarriage.

Diagnosis

In the case of blood loss, pain, or both, transvaginal ultrasound is performed. If a viable intrauterine pregnancy is not found with ultrasound, blood tests (serial βHCG tests) can be performed to rule out ectopic pregnancy, which is a life-threatening situation.

If hypotension, tachycardia, and anemia are discovered, exclusion of an ectopic pregnancy is important.

A miscarriage may be confirmed by an obstetric ultrasound and by the examination of the passed tissue. When looking for microscopic pathologic symptoms, one looks for the products of conception. Microscopically, these include villi, trophoblast, fetal parts, and background gestational changes in the endometrium. When chromosomal abnormalities are found in more than one miscarriage, genetic testing of both parents may be done.

Classification

A threatened miscarriage is any bleeding during the first half of pregnancy. At investigation it may be found that the fetus remains viable and the pregnancy continues without further problems.

An anembryonic pregnancy (also called an "empty sac" or "blighted ovum") is a condition where the gestational sac develops normally, while the embryonic part of the pregnancy is either absent or stops growing very early. This accounts for approximately half of miscarriages. All other miscarriages are classified as embryonic miscarriages, meaning that there is an embryo present in the gestational sac. Half of embryonic miscarriages have aneuploidy (an abnormal number of chromosomes).

An inevitable miscarriage occurs when the cervix has already dilated, but the fetus has yet to be expelled. This usually will progress to a complete miscarriage. The fetus may or may not have cardiac activity. 

Transvaginal ultrasonography after an episode of heavy bleeding in an intrauterine pregnancy that had been confirmed by a previous ultrasononography. There is some widening between the uterine walls, but no sign of any gestational sac, thus in this case being diagnostic of a complete miscarriage.

A complete miscarriage is when all products of conception have been expelled; these may include the trophoblast, chorionic villi, gestational sac, yolk sac, and fetal pole (embryo); or later in pregnancy the fetus, umbilical cord, placenta, amniotic fluid, and amniotic membrane. The presence of a pregnancy test that is still positive as well as an empty uterus upon transvaginal ultrasonography does, however, fulfill the definition of pregnancy of unknown location. Therefore, there may be a need for follow-up pregnancy tests to ensure that there is no remaining pregnancy, including an ectopic pregnancy.

Transvaginal ultrasonography, with some products of conception in the cervix (to the left in the image) and remnants of a gestational sac by the fundus (to the right in the image), indicating an incomplete miscarriage

An incomplete miscarriage occurs when some products of conception have been passed, but some remains inside the uterus. However, an increased distance between the uterine walls on transvaginal ultrasonography may also simply be an increased endometrial thickness and/or a polyp. The use of a Doppler ultrasound may be better in confirming the presence of significant retained products of conception in the uterine cavity. In cases of uncertainty, ectopic pregnancy must be excluded using techniques like serial beta-hCG measurements.

A 13-week fetus without cardiac activity located in the uterus (delayed or missed miscarriage)

A missed miscarriage is when the embryo or fetus has died, but a miscarriage has not yet occurred. It is also referred to as delayed miscarriage, silent miscarriage, or missed abortion.

A septic miscarriage occurs when the tissue from a missed or incomplete miscarriage becomes infected, which carries the risk of spreading infection (septicaemia) and can be fatal.

Recurrent miscarriage ("recurrent pregnancy loss" (RPL) or "habitual abortion") is the occurrence of multiple consecutive miscarriages; the exact number used to diagnose recurrent miscarriage varies. If the proportion of pregnancies ending in miscarriage is 15% and assuming that miscarriages are independent events, then the probability of two consecutive miscarriages is 2.25% and the probability of three consecutive miscarriages is 0.34%. The occurrence of recurrent pregnancy loss is 1%. A large majority (85%) of those who have had two miscarriages will conceive and carry normally afterward.

The physical symptoms of a miscarriage vary according to the length of pregnancy, though most miscarriages cause pain or cramping. The size of blood clots and pregnancy tissue that are passed become larger with longer gestations. After 13 weeks' gestation, there is a higher risk of placenta retention.

Prevention

Prevention of a miscarriage can sometimes be accomplished by decreasing risk factors. This may include good prenatal care, avoiding drugs and alcohol, preventing infectious diseases, and avoiding x-rays. Identifying the cause of the miscarriage may help prevent future pregnancy loss, especially in cases of recurrent miscarriage. Often there is little a person can do to prevent a miscarriage. Vitamin supplementation before or during pregnancy has not been found to affect the risk of miscarriage. Progesterone probably slightly reduces the risk of miscarriage in women with threatened miscarriage.

Non-modifiable risk factors

Preventing a miscarriage in subsequent pregnancies may be enhanced with assessments of:

• Immune status
• Chemical and occupational exposures
• Anatomical defects
• Intercurrent diseases
  • Polycystic ovary syndrome
• Previous exposure to chemotherapy and radiation
• Medications
• Surgical history
• Endocrine disorders
• Genetic abnormalities

Modifiable risk factors

Maintaining a healthy weight and good pre-natal care can reduce the risk of miscarriage. Some risk factors can be minimized by avoiding the following:

• Smoking
• Cocaine use
• Alcohol
• Poor nutrition
• Occupational exposure to agents that can cause miscarriage
• Medications associated with miscarriage
• Drug abuse

Management

Women who miscarry early in their pregnancy usually do not require any subsequent medical treatment but they can benefit from support and counseling. Most early miscarriages will complete on their own; in other cases, medication treatment or aspiration of the products of conception can be used to remove remaining tissue. While bed rest has been advocated to prevent miscarriage, this has not been found to be of benefit. Those who are or who have experienced an abortion benefit from the use of careful medical language. Significant distress can often be managed by the ability of the clinician to clearly explain terms without suggesting that the woman or couple are somehow to blame.

Evidence to support Rho(D) immune globulin after a spontaneous miscarriage is unclear. In the UK, Rho(D) immune globulin is recommended in Rh-negative women after 12 weeks gestational age and before 12 weeks gestational age in those who need surgery or medication to complete the miscarriage.

Methods

No treatment is necessary for a diagnosis of complete miscarriage (so long as ectopic pregnancy is ruled out). In cases of an incomplete miscarriage, empty sac, or missed abortion there are three treatment options: watchful waiting, medical management, and surgical treatment. With no treatment (watchful waiting), most miscarriages (65–80%) will pass naturally within two to six weeks.This treatment avoids the possible side effects and complications of medications and surgery, but increases the risk of mild bleeding, need for unplanned surgical treatment, and incomplete miscarriage. Medical treatment usually consists of using misoprostol (a prostaglandin) alone or in combination with mifepristone pre-treatment. These medications help the uterus to contract and expel the remaining tissue out of the body. This works within a few days in 95% of cases.Vacuum aspiration or sharp curettage can be used, though vacuum aspiration is lower-risk and more common.

Delayed and incomplete miscarriage

In delayed or incomplete miscarriage, treatment depends on the amount of tissue remaining in the uterus. Treatment can include surgical removal of the tissue with vacuum aspiration or misoprostol. Studies looking at the methods of anaesthesia for surgical management of incomplete miscarriage have not shown that any adaptation from normal practice is beneficial.

Induced miscarriage

An induced abortion may be performed by a qualified healthcare provider for women who cannot continue the pregnancy. Self-induced abortion performed by a woman or non-medical personnel can be dangerous and is still a cause of maternal mortality in some countries. In some locales it is illegal or carries heavy social stigma.However, in the United States, many choose to self-induce or self-manage their abortion and have done so safely.

Sex

Some organizations recommend delaying sex after a miscarriage until the bleeding has stopped to decrease the risk of infection. However, there is not sufficient evidence for the routine use of antibiotic to try to avoid infection in incomplete abortion. Others recommend delaying attempts at pregnancy until one period has occurred to make it easier to determine the dates of a subsequent pregnancy. There is no evidence that getting pregnancy in that first cycle however affects outcomes and an early subsequent pregnancy may actually improve outcomes.

Support

Organizations exist that provide information and counseling to help those who have had a miscarriage. Family and friends often conduct a memorial or burial service. Hospitals also can provide support and help memorialize the event. Depending on locale others desire to have a private ceremony. Providing appropriate support with frequent discussions and sympathetic counseling are part of evaluation and treatment. Those who experience unexplained miscarriage can be treated with emotional support.

Outcomes

Psychological and emotional effects

A cemetery for miscarried fetuses, stillborn babies, and babies who have died soon after birth

Every woman's personal experience of miscarriage is different, and women who have more than one miscarriage may react differently to each event.

In Western cultures since the 1980s, medical providers assume that experiencing a miscarriage "is a major loss for all pregnant women". A miscarriage can result in anxiety, depression or stress for those involved. It can have an effect on the whole family. Many of those experiencing a miscarriage go through a grieving process. "Prenatal attachment" often exists that can be seen as parental sensitivity, love and preoccupation directed toward the unborn child. Serious emotional impact is usually experienced immediately after the miscarriage. Some may go through the same loss when an ectopic pregnancy is terminated. In some, the realization of the loss can take weeks. Providing family support to those experiencing the loss can be challenging because some find comfort in talking about the miscarriage while others may find the event painful to discuss. The father can have the same sense of loss. Expressing feelings of grief and loss can sometimes be harder for men. Some women are able to begin planning their next pregnancy after a few weeks of having the miscarriage. For others, planning another pregnancy can be difficult. Some facilities acknowledge the loss. Parents can name and hold their infant. They may be given mementos such as photos and footprints. Some conduct a funeral or memorial service. They may express the loss by planting a tree.

Some health organizations recommend that sexual activity be delayed after the miscarriage. The menstrual cycle should resume after about three to four months. Women report that they were dissatisfied with the care they received from physicians and nurses.

Subsequent pregnancies

Some parents want to try to have a baby very soon after the miscarriage. The decision of trying to become pregnant again can be difficult. Reasons exist that may prompt parents to consider another pregnancy. For older mothers, there may be some sense of urgency. Other parents are optimistic that future pregnancies are likely to be successful. Many are hesitant and want to know about the risk of having another or more miscarriages. Some clinicians recommend that the women have one menstrual cycle before attempting another pregnancy. This is because the date of conception may be hard to determine. Also, the first menstrual cycle after a miscarriage can be much longer or shorter than expected. Parents may be advised to wait even longer if they have experienced late miscarriage or molar pregnancy, or are undergoing tests. Some parents wait for six months based upon recommendations from their health care provider.

The risks of having another miscarriage vary according to the cause. The risk of having another miscarriage after a molar pregnancy is very low. The risk of another miscarriage is highest after the third miscarriage. Pre-conception care is available in some locales.

Later cardiovascular disease

There is a significant association between miscarriage and later development of coronary artery disease, but not of cerebrovascular disease.

Epidemiology

Among women who know they are pregnant, the miscarriage rate is roughly 10% to 20%, while rates among all fertilized zygotes are around 30% to 50%. A 2012 review found the risk of miscarriage between 5 and 20 weeks from 11% to 22%. Up to the 13th week of pregnancy, the risk of miscarriage each week was around 2%, dropping to 1% in week 14 and reducing slowly between 14 and 20 weeks.

The precise rate is not known because a large number of miscarriages occur before pregnancies become established and before the woman is aware they are pregnant. Additionally, those with bleeding in early pregnancy may seek medical care more often than those not experiencing bleeding. Although some studies attempt to account for this by recruiting women who are planning pregnancies and testing for very early pregnancy, they still are not representative of the wider population.

The prevalence of miscarriage increases with the age of both parents. In a Danish register-based study where the prevalence of miscarriage was 11%, the prevalence rose from 9% at 22 years of age to 84% by 48 years of age. Another, later study in 2013 found that when either parent was over the age of 40, the rate of known miscarriages doubled.

In 2010, 50,000 inpatient admissions for miscarriage occurred in the UK.

Terminology

Most affected women and family members refer to miscarriage as the loss of a baby, rather than an embryo or fetus, and healthcare providers are expected to respect and use the language that the person chooses. Clinical terms can suggest blame, increase distress, and even cause anger. Terms that are known to cause distress in those experiencing miscarriage include:

• abortion (including spontaneous abortion) rather than miscarriage,
• habitual aborter rather than a woman experiencing recurrent pregnancy loss,
• products of conception rather than baby,
• blighted ovum rather than early pregnancy loss or delayed miscarriage,
• cervical incompetence rather than cervical weakness, and
• evacuation of retained products of conception (ERPC) rather than surgical management of miscarriage.

Pregnancy loss is a broad term that for miscarriage, ectopic and molar pregnancies. The term fetal death applies variably in different countries and contexts, sometimes incorporating weight, and gestational age from 16 weeks in Norway, 20 weeks in the US and Australia, 24 weeks in the UK to 26 weeks in Italy and Spain. A fetus that died before birth after this gestational age may be referred to as a stillbirth. Under UK law, all stillbirths should be registered, although this does not apply to miscarriages. 

History

The medical terminology applied to experiences during early pregnancy has changed over time. Before the 1980s, health professionals used the phrase spontaneous abortion for a miscarriage and induced abortion for a termination of the pregnancy. In the late 1980s and 1990s, doctors became more conscious of their language in relation to early pregnancy loss. Some medical authors advocated change to use of miscarriage instead of spontaneous abortion because they argued this would be more respectful and help ease a distressing experience. The change was being recommended by some in the profession in Britain in the late 1990s. In 2005 the European Society for Human Reproduction and Embryology (ESHRE) published a paper aiming to facilitate a revision of nomenclature used to describe early pregnancy events.

Society and culture

Society's reactions to miscarriage has changed over time. In the early 20th century, the focus was on the mother's physical health and the difficulties and disabilities that miscarriage could produce. Other reactions, such as the expense of medical treatments and relief at ending an unwanted pregnancy, were also heard. In the 1940s and 1950s, people were more likely to express relief, not because the miscarriage ended an unwanted or mistimed pregnancy, but because people believed that miscarriages were primarily caused by birth defects, and miscarrying meant that the family would not raise a child with disabilities. The dominant attitude in the mid-century was that a miscarriage, although temporarily distressing, was a blessing in disguise for the family, and that another pregnancy and a healthier baby would soon follow, especially if women trusted physicians and reduced their anxieties. Media articles were illustrated with pictures of babies, and magazine articles about miscarriage ended by introducing the healthy baby—usually a boy—that had shortly followed it.

Beginning in the 1980s, miscarriage in the US was primarily framed in terms of the individual woman's personal emotional reaction, and especially her grief over a tragic outcome. The subject was portrayed in the media with images of an empty crib or an isolated, grieving woman, and stories about miscarriage were published in general-interest media outlets, not just women's magazines or health magazines. Family members were encouraged to grieve, to memorialize their losses through funerals and other rituals, and to think of themselves as being parents. This shift to recognizing these emotional responses was partly due to medical and political successes, which created an expectation that pregnancies are typically planned and safe, and to women's demands that their emotional reactions no longer be dismissed by the medical establishments. It also reinforces the pro-life movement's belief that human life begins at conception or early in pregnancy, and that motherhood is a desirable life goal. The modern one-size-fits-all model of grief does not fit every woman's experience, and an expectation to perform grief creates unnecessary burdens for some women. The reframing of miscarriage as a private emotional experience brought less awareness of miscarriage and a sense of silence around the subject, especially compared to the public discussion of miscarriage during campaigns for access to birth control during the early 20th century, or the public campaigns to prevent miscarriages, stillbirths, and infant deaths by reducing industrial pollution during the 1970s.

In places where induced abortion is illegal or carries social stigma, suspicion may surround miscarriage, complicating an already sensitive issue.

In the 1960s, the use of the word miscarriage in Britain (instead of spontaneous abortion) occurred after changes in legislation. 

Developments in ultrasound technology (in the early 1980s) allowed them to identify earlier miscarriages.

According to French statutes, an infant born before the age of viability, determined to be 28 weeks, is not registered as a 'child'. If birth occurs after this, the infant is granted a certificate that allows women who have given birth to a stillborn child, to have a symbolic record of that child. This certificate can include a registered and given name with the purpose of allowing a funeral and acknowledgement of the event.

Other animals

Miscarriage occurs in all animals that experience pregnancy, though in such contexts it is more commonly referred to as a "spontaneous abortion" (the two terms are synonymous). There are a variety of known risk factors in non-human animals. For example, in sheep, miscarriage may be caused by crowding through doors, or being chased by dogs. In cows, spontaneous abortion may be caused by contagious disease, such as brucellosis or Campylobacter, but often can be controlled by vaccination. In many species of sharks and rays, stress induced miscarriage occurs frequently on capture.

Other diseases are also known to make animals susceptible to miscarriage. Spontaneous abortion occurs in pregnant prairie voles when their mate is removed and they are exposed to a new male, an example of the Bruce effect, although this effect is seen less in wild populations than in the laboratory. Female mice who had spontaneous abortions showed a sharp rise in the amount of time spent with unfamiliar males preceding the abortion than those who did not.