High-altitude adaptation in humans is an instance of evolutionary modification in certain human populations, including those of Tibet in Asia, the Andes of the Americas, and Ethiopia in Africa, who have acquired the ability to survive at altitudes above 2,500 meters. This adaptation means irreversible, long-term physiological responses to high-altitude environments, associated with heritable behavioural and genetic changes.
While the rest of the human population would suffer serious health
consequences, the indigenous inhabitants of these regions thrive well in
the highest parts of the world. These people have undergone extensive
physiological and genetic changes, particularly in the regulatory
systems of oxygen respiration and blood circulation, when compared to the general lowland population.
Around 81.6 million people, approximately 1.1% of the world's human population, live permanently at altitudes above 2,500 metres (8,200 ft) putting these populations at risk for chronic mountain sickness (CMS). However, the high-altitude populations in South America, East Africa, and South Asia have done so for millennia without apparent complications. This special adaptation is now recognised as an example of natural selection in action. The adaptation of the Tibetans is the fastest known example of human evolution, as it is estimated to have occurred any time around 1,000 B.C.E. to 7,000 B.C.E.
Origin and basis
Himalayas, on the southern rim of the Tibetan Plateau
An estimated 81.6 million people worldwide are estimated to live
at an elevation higher than 2,500 metres (8,200 ft) above sea level, of
which 21.7 million are in Ethiopia, 12.5 million in China, 11.7 million in Colombia, 7.8 million in Peru and 6.2 million in Bolivia.
Certain natives of Tibet, Ethiopia, and the Andes have been living at
these high altitudes for generations and are protected from hypoxia as a
consequence of genetic adaptation. It is estimated that at 4,000 metres (13,000 ft), every lungful of air only has 60% of the oxygen molecules that people at sea level have. Highlanders are thus constantly exposed to a low oxygen environment, yet they live without any debilitating problems. One of the best documented effects of high altitude is a progressive reduction in birth weight.
It has been known that women of long-resident high-altitude population
are not affected. These women are known to give birth to heavier-weight
infants than women of lowland inhabitants. This is particularly true
among Tibetan babies, whose average birth weight is 294–650 (~470) g
heavier than the surrounding Chinese population; and their blood-oxygen level is considerably higher.
Scientists started to notice the extraordinary physical performance
of Tibetans since the beginning of Himalayan climbing era in the early
20th century. The hypothesis of a possible evolutionary genetic
adaptation makes sense. The Tibetan plateau has an average elevation of 4,000 metres (13,000 ft) above sea level, and covering more than 2.5 million km2, it is the highest and largest plateau
in the world. In 1990, it was estimated that 4,594,188 Tibetans live on
the plateau, with 53% living at an altitude over 3,500 metres
(11,500 ft). Fairly large numbers (about 600,000) live at an altitude
exceeding 4,500 metres (14,800 ft) in the Chantong-Qingnan area.
Where the Tibetan highlanders live, the oxygen level is only about 60%
of that at sea level. The Tibetans, who have been living in this region
for 3,000 years, do not exhibit the elevated haemoglobin concentrations
to cope with oxygen deficiency as observed in other populations who have
moved temporarily or permanently at high altitudes. Instead, the
Tibetans inhale more air with each breath and breathe more rapidly than
either sea-level populations or Andeans. Tibetans have better oxygenation at birth, enlarged lung volumes throughout life, and a higher capacity for exercise. They show a sustained increase in cerebral blood flow, lower haemoglobin concentration, and less susceptibility to chronic mountain sickness than other populations, due to their longer history of high-altitude habitation.
Individuals can develop short-term tolerance with careful
physical preparation and systematic monitoring of movements, but the
biological changes are quite temporary and reversible when they return
to lowlands. Moreover, unlike lowland people who only experience increased breathing
for a few days after entering high altitudes, Tibetans retain this
rapid breathing and elevated lung-capacity throughout their lifetime.
This enables them to inhale larger amounts of air per unit of time to
compensate for low oxygen levels. In addition, they have high levels
(mostly double) of nitric oxide in their blood, when compared to lowlanders, and this probably helps their blood vessels dilate for enhanced blood circulation. Further, their haemoglobin level is not significantly different (average 15.6 g/dl in males and 14.2 g/dl in females),
from those of people living at low altitude. (Normally, mountaineers
experience >2 g/dl increase in Hb level at Mt. Everest base camp in
two weeks.)
In this way they are able to evade both the effects of hypoxia and
mountain sickness throughout life. Even when they climbed the highest
summits like Mt. Everest, they showed regular oxygen uptake, greater
ventilation, more brisk hypoxic ventilatory responses, larger lung
volumes, greater diffusing capacities, constant body weight and a better
quality of sleep, compared to people from the lowland.
Andeans
In
contrast to the Tibetans, the Andean highlanders, who have been living
at high altitudes for no more than 11,000 years, show different pattern
of haemoglobin adaptation. Their haemoglobin concentration is higher
compared to those of lowlander population, which also happens to
lowlanders moving to high altitude. When they spend some weeks in the
lowland their haemoglobin drops to average of other people. This shows
only temporary and reversible acclimatisation. However, in contrast to
lowland people, they do have increased oxygen level in their
haemoglobin, that is, more oxygen per blood volume than other people.
This confers an ability to carry more oxygen in each red blood cell,
making a more effective transport of oxygen in their body, while their
breathing is essentially at the same rate.
This enables them to overcome hypoxia and normally reproduce without
risk of death for the mother or baby. The Andean highlanders are known
from the 16th-century missionaries that their reproduction had always
been normal, without any effect in the giving birth or the risk for early pregnancy loss, which are common to hypoxic stress. They have developmentally acquired enlarged residual lung volume and its associated increase in alveolar area, which are supplemented with increased tissue thickness and moderate increase in red blood cells. Though the physical growth in body size is delayed, growth in lung volumes is accelerated. An incomplete adaptation such as elevated haemoglobin levels still leaves them at risk for mountain sickness with old age.
Quechua woman with llamas
Among the Quechua people of the Altiplano, there is a significant variation in NOS3 (the gene encoding endothelial nitric oxide synthase, eNOS), which is associated with higher levels of nitric oxide in high altitude.
Nuñoa children of Quechua ancestry exhibit higher blood-oxygen content
(91.3) and lower heart rate (84.8) than their counterpart school
children of different ethnicity, who have an average of 89.9
blood-oxygen and 88–91 heart rate. High-altitude born and bred females of Quechua origins have comparatively enlarged lung volume for increased respiration.
Aymara ceremony
Blood profile comparisons show that among the Andeans, Aymaran highlanders are better adapted to highlands than the Quechuas. Among the Bolivian
Aymara people, the resting ventilation and hypoxic ventilatory response
were quite low (roughly 1.5 times lower), in contrast to those of the
Tibetans. The intrapopulation genetic variation was relatively less
among the Aymara people.
Moreover, when compared to Tibetans, the blood haemoglobin level at
high altitudes among Aymarans is notably higher, with an average of
19.2 g/dl for males and 17.8 g/dl for females.
Among the different native highlander populations, the underlying
physiological responses to adaptation are quite different. For example,
among four quantitative features, such as are resting ventilation,
hypoxic ventilatory response, oxygen saturation, and haemoglobin
concentration, the levels of variations are significantly different
between the Tibetans and the Aymaras. Methylation also influences oxygenation.
Ethiopians
The peoples of the Ethiopian highlands
also live at extremely high altitudes, around 3,000 metres (9,800 ft)
to 3,500 metres (11,500 ft). Highland Ethiopians exhibit elevated
haemoglobin levels, like Andeans and lowlander peoples at high
altitudes, but do not exhibit the Andeans’ increase in oxygen content of
haemoglobin.
Among healthy individuals, the average haemoglobin concentrations are
15.9 and 15.0 g/dl for males and females respectively (which is lower
than normal, almost similar to the Tibetans), and an average oxygen
saturation of haemoglobin is 95.3% (which is higher than average, like
the Andeans).
Additionally, Ethiopian highlanders do not exhibit any significant
change in blood circulation of the brain, which has been observed among
the Peruvian highlanders (and attributed to their frequent
altitude-related illnesses).
Yet, similar to the Andeans and Tibetans, the Ethiopian highlanders are
immune to the extreme dangers posed by high-altitude environment, and
their pattern of adaptation is definitely unique from that of other
highland peoples.
Genetic basis
The underlying molecular evolution of high-altitude adaptation has been explored and understood fairly recently.
Depending on the geographical and environmental pressures,
high-altitude adaptation involves different genetic patterns, some of
which
have evolved quite recently. For example, Tibetan adaptations became
prevalent in the past 3,000 years, a rapid example of recent human evolution.
At the turn of the 21st century, it was reported that the genetic
make-up of the respiratory components of the Tibetan and the Ethiopian
populations are significantly different.
Tibetans
Substantial evidence in Tibetan highlanders suggests that variation in haemoglobin and blood-oxygen levels are adaptive as Darwinian fitness. It has been documented that Tibetan women with a high likelihood of possessing one to two alleles
for high blood-oxygen content (which is odd for normal women) had more
surviving children; the higher the oxygen capacity, the lower the infant
mortality.
In 2010, for the first time, the genes responsible for the unique
adaptive traits were identified following genome sequencing of 50
Tibetans and 40 Han Chinese from Beijing.
Initially, the strongest signal of natural selection detected was a
transcription factor involved in response to hypoxia, called endothelial
Per-Arnt-Sim (PAS) domain protein 1 (EPAS1). It was found that one single-nucleotide polymorphism (SNP) at EPAS1
shows a 78% frequency difference between Tibetan and mainland Chinese
samples, representing the fastest genetic change observed in any human
gene to date. Hence, Tibetan adaptation to high altitude becomes the
fastest process of phenotypically observable evolution in humans,
which is estimated to have occurred a few thousand years ago, when the
Tibetans split up from the mainland Chinese population. The time of
genetic divergence has been variously estimated as 2,750 (original
estimate), 4,725, 8,000, or 9,000 years ago. Mutations in EPAS1,
at higher frequency in Tibetans than their Han neighbours, correlate
with decreased haemoglobin concentrations among the Tibetans, which is
the hallmark of their adaptation to hypoxia. Simultaneously, two genes,
egl nine homolog 1 (EGLN1) (which inhibits haemoglobin production under high oxygen concentration) and peroxisome proliferator-activated receptor alpha (PPARA), were also identified to be positively selected in relation to decreased haemoglobin nature in the Tibetans.
Similarly, the Sherpas, known for their Himalayan hardiness, exhibit similar patterns in the EPAS1 gene, which further fortifies that the gene is under selection for adaptation to the high-altitude life of Tibetans. A study in 2014 indicates that the mutant EPAS1 gene could have been inherited from archaic hominins, the Denisovans. EPAS1 and EGLN1 are definitely the major genes for unique adaptive traits when compared with those of the Chinese and Japanese.
Comparative genome analysis in 2014 revealed that the Tibetans
inherited an equal mixture of genomes from the Nepalese-Sherpas and
Hans, and they acquired the adaptive genes from the sherpa-lineage.
Further, the population split was estimated to occur around 20,000 to
40,000 years ago, a range of which support archaeological, mitochondria
DNA and Y chromosome evidence for an initial colonisation of the Tibetan
plateau around 30,000 years ago.
The genes (EPAS1, EGLN1, and PPARA) function in concert with another gene named hypoxia inducible factors (HIF), which in turn is a principal regulator of red blood cell production (erythropoiesis) in response to oxygen metabolism.The genes are associated not only with decreased haemoglobin levels, but also in regulating energy metabolism. EPAS1 is significantly associated with increased lactate concentration (the product of anaerobic glycolysis), and PPARA is correlated with decrease in the activity of fatty acid oxidation. EGLN1 codes for an enzyme, prolyl hydroxylase 2 (PHD2), involved in erythropoiesis. Among the Tibetans, mutation in EGLN1
(specifically at position 12, where cytosine is replaced with guanine;
and at 380, where G is replaced with C) results in mutant PHD2 (aspartic
acid at position 4 becomes glutamine, and cysteine at 127 becomes
serine) and this mutation inhibits erythropoiesis. The mutation is
estimated to occur about 8,000 years ago. Further, the Tibetans are enriched for genes in the disease class of human reproduction (such as genes from the DAZ, BPY2, CDY, and HLA-DQ and HLA-DR gene clusters) and biological process categories of response to DNA damage stimulus and DNA repair (such as RAD51, RAD52, and MRE11A), which are related to the adaptive traits of high infant birth weight and darker skin tone and are most likely due to recent local adaptation.
Andeans
The
patterns of genetic adaptation among the Andeans are largely distinct
from those of the Tibetan, with both populations showing evidence of
positive natural selection in different genes or gene regions. However, EGLN1
appears to be the principal signature of evolution, as it shows
evidence of positive selection in both Tibetans and Andeans. Even then,
the pattern of variation for this gene differs between the two
populations. Among the Andeans, there are no significant associations between EPAS1 or EGLN1 SNP genotypes and haemoglobin concentration, which has been the characteristic of the Tibetans.
The whole genome sequences of 20 Andeans (half of them having chronic
mountain sickness) revealed that two genes, SENP1 (an erythropoiesis
regulator) and ANP32D (an oncogene) play vital roles in their weak
adaptation to hypoxia.
Ethiopians
The
adaptive mechanism of Ethiopian highlanders is quite different. This is
probably because their migration to the highland was relatively early;
for example, the Amhara
have inhabited altitudes above 2,500 metres (8,200 ft) for at least
5,000 years and altitudes around 2,000 metres (6,600 ft) to 2,400 metres
(7,900 ft) for more than 70,000 years. Genomic analysis of two ethnic groups, Amhara and Oromo, revealed that gene variations associated with haemoglobin difference among Tibetans or other variants at the same gene location do not influence the adaptation in Ethiopians. Identification of specific genes further reveals that several candidate genes are involved in Ethiopians, including CBARA1, VAV3, ARNT2 and THRB. Two of these genes (THRB and ARNT2) are known to play a role in the HIF-1 pathway,
a pathway implicated in previous work reported in Tibetan and Andean
studies. This supports the concept that adaptation to high altitude
arose independently among different highlanders as a result of convergent evolution.
A gene is a region of DNA that encodes function. A chromosome consists of a long strand of DNA containing many genes. A human chromosome can have up to 500 million base pairs of DNA with thousands of genes.
During gene expression, the DNA is first copied into RNA. The RNA can be directly functional or be the intermediate template for a protein that performs a function. The transmission of genes to an organism's offspring is the basis of the inheritance of phenotypic traits. These genes make up different DNA sequences called genotypes.
Genotypes along with environmental and developmental factors determine
what the phenotypes will be. Most biological traits are under the
influence of polygenes (many different genes) as well as gene–environment interactions. Some genetic traits are instantly visible, such as eye color or the number of limbs, and some are not, such as blood type, the risk for specific diseases, or the thousands of basic biochemical processes that constitute life.
Genes can acquire mutations in their sequence, leading to different variants, known as alleles, in the population. These alleles encode slightly different versions of a protein, which cause different phenotypical
traits. Usage of the term "having a gene" (e.g., "good genes," "hair
color gene") typically refers to containing a different allele of the
same, shared gene. Genes evolve due to natural selection / survival of the fittest and genetic drift of the alleles.
The concept of gene continues to be refined as new phenomena are discovered. For example, regulatory regions of a gene can be far removed from its coding regions, and coding regions can be split into several exons. Some viruses store their genome in RNA instead of DNA and some gene products are functional non-coding RNAs. Therefore, a broad, modern working definition of a gene is any discrete locus of heritable, genomic sequence which affect an organism's traits by being expressed as a functional product or by regulation of gene expression.
The term gene was introduced by Danish botanist, plant physiologist and geneticistWilhelm Johannsen in 1909. It is inspired by the ancient Greek: γόνος, gonos, that means offspring and procreation.
The existence of discrete inheritable units was first suggested by Gregor Mendel (1822–1884). From 1857 to 1864, in Brno, Austrian Empire (today's Czech Republic), he studied inheritance patterns in 8000 common edible pea plants, tracking distinct traits from parent to offspring. He described these mathematically as 2n combinations where n is the number of differing characteristics in the original peas. Although he did not use the term gene,
he explained his results in terms of discrete inherited units that give
rise to observable physical characteristics. This description
prefigured Wilhelm Johannsen's distinction between genotype (the genetic material of an organism) and phenotype (the observable traits of that organism). Mendel was also the first to demonstrate independent assortment, the distinction between dominant and recessive traits, the distinction between a heterozygote and homozygote, and the phenomenon of discontinuous inheritance.
Prior to Mendel's work, the dominant theory of heredity was one of blending inheritance,
which suggested that each parent contributed fluids to the
fertilisation process and that the traits of the parents blended and
mixed to produce the offspring. Charles Darwin developed a theory of inheritance he termed pangenesis, from Greek pan ("all, whole") and genesis ("birth") / genos ("origin"). Darwin used the term gemmule to describe hypothetical particles that would mix during reproduction.
Mendel's work went largely unnoticed after its first publication in 1866, but was rediscovered in the late 19th century by Hugo de Vries, Carl Correns, and Erich von Tschermak, who (claimed to have) reached similar conclusions in their own research. Specifically, in 1889, Hugo de Vries published his book Intracellular Pangenesis,
in which he postulated that different characters have individual
hereditary carriers and that inheritance of specific traits in organisms
comes in particles. De Vries called these units "pangenes" (Pangens in German), after Darwin's 1868 pangenesis theory.
Twenty years later, in 1909, Wilhelm Johannsen introduced the term 'gene' and in 1906, William Bateson, that of 'genetics' while Eduard Strasburger, amongst others, still used the term 'pangene' for the fundamental physical and functional unit of heredity.
Discovery of DNA
Advances in understanding genes and inheritance continued throughout the 20th century. Deoxyribonucleic acid (DNA) was shown to be the molecular repository of genetic information by experiments in the 1940s to 1950s. The structure of DNA was studied by Rosalind Franklin and Maurice Wilkins using X-ray crystallography, which led James D. Watson and Francis Crick to publish a model of the double-stranded DNA molecule whose paired nucleotide bases indicated a compelling hypothesis for the mechanism of genetic replication.
In the early 1950s the prevailing view was that the genes in a
chromosome acted like discrete entities, indivisible by recombination
and arranged like beads on a string. The experiments of Benzer using mutants defective in the rII region of bacteriophage T4
(1955–1959) showed that individual genes have a simple linear structure
and are likely to be equivalent to a linear section of DNA.
In 1972, Walter Fiers and his team were the first to determine the sequence of a gene: that of Bacteriophage MS2 coat protein. The subsequent development of chain-terminationDNA sequencing in 1977 by Frederick Sanger improved the efficiency of sequencing and turned it into a routine laboratory tool. An automated version of the Sanger method was used in early phases of the Human Genome Project.
Evolutionary biologists have subsequently modified this concept, such as George C. Williams' gene-centric view of evolution. He proposed an evolutionary concept of the gene as a unit of natural selection with the definition: "that which segregates and recombines with appreciable frequency." In this view, the molecular gene transcribes as a unit, and the evolutionary gene inherits as a unit. Related ideas emphasizing the centrality of genes in evolution were popularized by Richard Dawkins.
The vast majority of organisms encode their genes in long strands of DNA (deoxyribonucleic acid). DNA consists of a chain made from four types of nucleotide subunits, each composed of: a five-carbon sugar (2-deoxyribose), a phosphate group, and one of the four basesadenine, cytosine, guanine, and thymine.
Two chains of DNA twist around each other to form a DNA double helix with the phosphate-sugar backbone spiraling around the outside, and the bases pointing inwards with adenine base pairing to thymine and guanine to cytosine. The specificity of base pairing occurs because adenine and thymine align to form two hydrogen bonds, whereas cytosine and guanine form three hydrogen bonds. The two strands in a double helix must, therefore, be complementary,
with their sequence of bases matching such that the adenines of one
strand are paired with the thymines of the other strand, and so on.
Due to the chemical composition of the pentose residues of the bases, DNA strands have directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose; this is known as the 3' end of the molecule. The other end contains an exposed phosphate group; this is the 5' end. The two strands of a double-helix run in opposite directions. Nucleic acid synthesis, including DNA replication and transcription occurs in the 5'→3' direction, because new nucleotides are added via a dehydration reaction that uses the exposed 3' hydroxyl as a nucleophile.
The expression of genes encoded in DNA begins by transcribing the gene into RNA, a second type of nucleic acid that is very similar to DNA, but whose monomers contain the sugar ribose rather than deoxyribose. RNA also contains the base uracil in place of thymine.
RNA molecules are less stable than DNA and are typically
single-stranded. Genes that encode proteins are composed of a series of
three-nucleotide sequences called codons, which serve as the "words" in the genetic "language". The genetic code specifies the correspondence during protein translation between codons and amino acids. The genetic code is nearly the same for all known organisms.
Chromosomes
Fluorescent microscopy image of a human female karyotype, showing 23 pairs of chromosomes. The DNA is stained red, with regions rich in housekeeping genes further stained in green. The largest chromosomes are around 10 times the size of the smallest.
The total complement of genes in an organism or cell is known as its genome, which may be stored on one or more chromosomes. A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded. The region of the chromosome at which a particular gene is located is called its locus. Each locus contains one allele
of a gene; however, members of a population may have different alleles
at the locus, each with a slightly different gene sequence.
The majority of eukaryotic genes are stored on a set of large, linear chromosomes. The chromosomes are packed within the nucleus in complex with storage proteins called histones to form a unit called a nucleosome. DNA packaged and condensed in this way is called chromatin.
The manner in which DNA is stored on the histones, as well as chemical
modifications of the histone itself, regulate whether a particular
region of DNA is accessible for gene expression.
In addition to genes, eukaryotic chromosomes contain sequences involved
in ensuring that the DNA is copied without degradation of end regions
and sorted into daughter cells during cell division: replication origins, telomeres and the centromere. Replication origins are the sequence regions where DNA replication
is initiated to make two copies of the chromosome. Telomeres are long
stretches of repetitive sequences that cap the ends of the linear
chromosomes and prevent degradation of coding and regulatory regions
during DNA replication. The length of the telomeres decreases each time the genome is replicated and has been implicated in the aging process. The centromere is required for binding spindle fibres to separate sister chromatids into daughter cells during cell division.
Prokaryotes (bacteria and archaea) typically store their genomes on a single large, circular chromosome. Similarly, some eukaryotic organelles contain a remnant circular chromosome with a small number of genes. Prokaryotes sometimes supplement their chromosome with additional small circles of DNA called plasmids, which usually encode only a few genes and are transferable between individuals. For example, the genes for antibiotic resistance are usually encoded on bacterial plasmids and can be passed between individual cells, even those of different species, via horizontal gene transfer.
Whereas the chromosomes of prokaryotes are relatively gene-dense,
those of eukaryotes often contain regions of DNA that serve no obvious
function. Simple single-celled eukaryotes have relatively small amounts
of such DNA, whereas the genomes of complex multicellular organisms, including humans, contain an absolute majority of DNA without an identified function. This DNA has often been referred to as "junk DNA". However, more recent analyses suggest that, although protein-coding DNA makes up barely 2% of the human genome, about 80% of the bases in the genome may be expressed, so the term "junk DNA" may be a misnomer.
The structure of a eukaryotic protein-coding gene. Regulatory sequence controls when and where expression occurs for the protein coding region (red). Promoter and enhancer regions (yellow) regulate the transcription of the gene into a pre-mRNA which is modified to remove introns (light grey) and add a 5' cap and poly-A tail (dark grey). The mRNA 5' and 3' untranslated regions (blue) regulate translation into the final protein product.
The structure of a gene consists of many elements of which the actual protein coding sequence is often only a small part. These include DNA regions that are not transcribed as well as untranslated regions of the RNA.
Flanking the open reading frame, genes contain a regulatory sequence that is required for their expression. First, genes require a promoter sequence. The promoter is recognized and bound by transcription factors that recruit and help RNA polymerase bind to the region to initiate transcription. The recognition typically occurs as a consensus sequence like the TATA box. A gene can have more than one promoter, resulting in messenger RNAs (mRNA) that differ in how far they extend in the 5' end.
Highly transcribed genes have "strong" promoter sequences that form
strong associations with transcription factors, thereby initiating
transcription at a high rate. Others genes have "weak" promoters that
form weak associations with transcription factors and initiate
transcription less frequently.Eukaryoticpromoter regions are much more complex and difficult to identify than prokaryotic promoters.
Additionally, genes can have regulatory regions many kilobases
upstream or downstream of the open reading frame that alter expression.
These act by binding
to transcription factors which then cause the DNA to loop so that the
regulatory sequence (and bound transcription factor) become close to the
RNA polymerase binding site. For example, enhancers increase transcription by binding an activator protein which then helps to recruit the RNA polymerase to the promoter; conversely silencers bind repressor proteins and make the DNA less available for RNA polymerase.
The transcribed pre-mRNA contains untranslated regions at both ends which contain binding sites for ribosomes, RNA-binding proteins, miRNA, as well as terminator, and start and stop codons. In addition, most eukaryotic open reading frames contain untranslated introns, which are removed and exons, which are connected together in a process known as RNA splicing. Finally, the ends of gene transcripts are defined by cleavage and polyadenylation (CPA) sites, where newly produced pre-mRNA gets cleaved and a string of ~200 adenosine monophosphates is added at the 3′ end. The poly(A)
tail protects mature mRNA from degradation and has other functions,
affecting translation, localization, and transport of the transcript
from the nucleus. Splicing, followed by CPA, generate the final mature mRNA, which encodes the protein or RNA product.
Although the general mechanisms defining locations of human genes are
known, identification of the exact factors regulating these cellular
processes is an area of active research. For example, known sequence
features in the 3′-UTR can only explain half of all human gene ends.
Many prokaryotic genes are organized into operons, with multiple protein-coding sequences that are transcribed as a unit. The genes in an operon are transcribed as a continuous messenger RNA, referred to as a polycistronic mRNA. The term cistron in this context is equivalent to gene. The transcription of an operon's mRNA is often controlled by a repressor that can occur in an active or inactive state depending on the presence of specific metabolites. When active, the repressor binds to a DNA sequence at the beginning of the operon, called the operator region, and represses transcription of the operon; when the repressor is inactive transcription of the operon can occur (see e.g. Lac operon). The products of operon genes typically have related functions and are involved in the same regulatory network.
Functional definitions
Defining exactly what section of a DNA sequence comprises a gene is difficult.Regulatory regions of a gene such as enhancers do not necessarily have to be close to the coding sequence
on the linear molecule because the intervening DNA can be looped out to
bring the gene and its regulatory region into proximity. Similarly, a
gene's introns can be much larger than its exons. Regulatory regions can
even be on entirely different chromosomes and operate in trans to allow regulatory regions on one chromosome to come in contact with target genes on another chromosome.
Early work in molecular genetics suggested the concept that one gene makes one protein. This concept (originally called the one gene-one enzyme hypothesis) emerged from an influential 1941 paper by George Beadle and Edward Tatum on experiments with mutants of the fungus Neurospora crassa. Norman Horowitz, an early colleague on the Neurospora research, reminisced in 2004 that “these experiments founded the science of what Beadle and Tatum called biochemical genetics. In actuality they proved to be the opening gun in what became molecular genetics and all the developments that have followed from that.” The one gene-one protein concept has been refined since the discovery of genes that can encode multiple proteins by alternative splicing and coding sequences split in short section across the genome whose mRNAs are concatenated by trans-splicing.
A broad operational definition is sometimes used to encompass the
complexity of these diverse phenomena, where a gene is defined as a
union of genomic sequences encoding a coherent set of potentially
overlapping functional products.
This definition categorizes genes by their functional products
(proteins or RNA) rather than their specific DNA loci, with regulatory
elements classified as gene-associated regions.
Overlap between genes
It is also possible for genes to overlap the same DNA sequence and be considered distinct but overlapping genes.
The current definition of an overlapping gene is different across
eukaryotes, prokaryotes, and viruses. In Eukaryotes they have recently
been defined as "when at least one nucleotide is shared between the
outermost boundaries of the primary transcripts
of two or more genes, such that a DNA base mutation at the point of
overlap would affect transcripts of all genes involved in the overlap."
In Prokaryotes and Viruses they have recently been defined as "when the coding sequences of two genes share a nucleotide either on the same or opposite strands."
In all organisms, two steps are required to read the information
encoded in a gene's DNA and produce the protein it specifies. First, the
gene's DNA is transcribed to messenger RNA (mRNA).Second, that mRNA is translated to protein. RNA-coding genes must still go through the first step, but are not translated into protein. The process of producing a biologically functional molecule of either RNA or protein is called gene expression, and the resulting molecule is called a gene product.
Genetic code
Schematic of a single-stranded RNA molecule illustrating a series of three-base codons. Each three-nucleotide codon corresponds to an amino acid when translated to protein
The nucleotide sequence of a gene's DNA specifies the amino acid sequence of a protein through the genetic code. Sets of three nucleotides, known as codons, each correspond to a specific amino acid.
The principle that three sequential bases of DNA code for each amino
acid was demonstrated in 1961 using frameshift mutations in the rIIB
gene of bacteriophage T4.
Additionally, a "start codon", and three "stop codons" indicate the beginning and end of the protein coding region. There are 64 possible codons (four possible nucleotides at each of three positions, hence 43 possible
codons) and only 20 standard amino acids; hence the code is redundant
and multiple codons can specify the same amino acid. The correspondence
between codons and amino acids is nearly universal among all known
living organisms.
Transcription
Transcription produces a single-stranded RNA molecule known as messenger RNA, whose nucleotide sequence is complementary to the DNA from which it was transcribed.
The mRNA acts as an intermediate between the DNA gene and its final
protein product. The gene's DNA is used as a template to generate a complementary mRNA. The mRNA matches the sequence of the gene's DNA coding strand because it is synthesised as the complement of the template strand. Transcription is performed by an enzyme called an RNA polymerase, which reads the template strand in the 3' to 5' direction and synthesizes the RNA from 5' to 3'. To initiate transcription, the polymerase first recognizes and binds a promoter region of the gene. Thus, a major mechanism of gene regulation is the blocking or sequestering the promoter region, either by tight binding by repressor molecules that physically block the polymerase or by organizing the DNA so that the promoter region is not accessible.
In prokaryotes, transcription occurs in the cytoplasm; for very long transcripts, translation may begin at the 5' end of the RNA while the 3' end is still being transcribed. In eukaryotes,
transcription occurs in the nucleus, where the cell's DNA is stored.
The RNA molecule produced by the polymerase is known as the primary transcript and undergoes post-transcriptional modifications before being exported to the cytoplasm for translation. One of the modifications performed is the splicing of introns which are sequences in the transcribed region that do not encode a protein. Alternative splicing
mechanisms can result in mature transcripts from the same gene having
different sequences and thus coding for different proteins. This is a
major form of regulation in eukaryotic cells and also occurs in some
prokaryotes.
Translation
Protein coding genes are transcribed to an mRNA intermediate, then translated to a functional protein. RNA-coding genes are transcribed to a functional non-coding RNA. (PDB: 3BSE, 1OBB, 3TRA)
Translation is the process by which a mature mRNA molecule is used as a template for synthesizing a new protein. Translation is carried out by ribosomes, large complexes of RNA and protein responsible for carrying out the chemical reactions to add new amino acids to a growing polypeptide chain by the formation of peptide bonds. The genetic code is read three nucleotides at a time, in units called codons, via interactions with specialized RNA molecules called transfer RNA (tRNA). Each tRNA has three unpaired bases known as the anticodon that are complementary to the codon it reads on the mRNA. The tRNA is also covalently attached to the amino acid
specified by the complementary codon. When the tRNA binds to its
complementary codon in an mRNA strand, the ribosome attaches its amino
acid cargo to the new polypeptide chain, which is synthesized from amino terminus to carboxyl terminus. During and after synthesis, most new proteins must fold to their active three-dimensional structure before they can carry out their cellular functions.
A typical protein-coding gene is first copied into RNA as an intermediate in the manufacture of the final protein product. In other cases, the RNA molecules are the actual functional products, as in the synthesis of ribosomal RNA and transfer RNA. Some RNAs known as ribozymes are capable of enzymatic function, and microRNA has a regulatory role. The DNA sequences from which such RNAs are transcribed are known as non-coding RNA genes.
Some viruses store their entire genomes in the form of RNA, and contain no DNA at all. Because they use RNA to store genes, their cellularhosts may synthesize their proteins as soon as they are infected and without the delay in waiting for transcription. On the other hand, RNA retroviruses, such as HIV, require the reverse transcription of their genome from RNA into DNA before their proteins can be synthesized. RNA-mediated epigenetic inheritance has also been observed in plants and very rarely in animals.
Inheritance
Inheritance of a gene that has two different alleles (blue and white). The gene is located on an autosomal chromosome. The white allele is recessive to the blue allele. The probability of each outcome in the children's generation is one quarter, or 25 percent.
Organisms inherit their genes from their parents. Asexual organisms simply inherit a complete copy of their parent's genome. Sexual organisms have two copies of each chromosome because they inherit one complete set from each parent.
Mendelian inheritance
According to Mendelian inheritance, variations in an organism's phenotype (observable physical and behavioral characteristics) are due in part to variations in its genotype (particular set of genes). Each gene specifies a particular trait with a different sequence of a gene (alleles)
giving rise to different phenotypes. Most eukaryotic organisms (such as
the pea plants Mendel worked on) have two alleles for each trait, one
inherited from each parent.
Alleles at a locus may be dominant or recessive;
dominant alleles give rise to their corresponding phenotypes when
paired with any other allele for the same trait, whereas recessive
alleles give rise to their corresponding phenotype only when paired with
another copy of the same allele. If you know the genotypes of the
organisms, you can determine which alleles are dominant and which are
recessive. For example, if the allele specifying tall stems in pea
plants is dominant over the allele specifying short stems, then pea
plants that inherit one tall allele from one parent and one short allele
from the other parent will also have tall stems. Mendel's work
demonstrated that alleles assort independently in the production of gametes, or germ cells,
ensuring variation in the next generation. Although Mendelian
inheritance remains a good model for many traits determined by single
genes (including a number of well-known genetic disorders) it does not include the physical processes of DNA replication and cell division.
DNA replication and cell division
The growth, development, and reproduction of organisms relies on cell division; the process by which a single cell divides into two usually identical daughter cells. This requires first making a duplicate copy of every gene in the genome in a process called DNA replication. The copies are made by specialized enzymes known as DNA polymerases,
which "read" one strand of the double-helical DNA, known as the
template strand, and synthesize a new complementary strand. Because the
DNA double helix is held together by base pairing,
the sequence of one strand completely specifies the sequence of its
complement; hence only one strand needs to be read by the enzyme to
produce a faithful copy. The process of DNA replication is semiconservative; that is, the copy of the genome inherited by each daughter cell contains one original and one newly synthesized strand of DNA.
The rate of DNA replication in living cells was first measured as the rate of phage T4 DNA elongation in phage-infected E. coli and found to be impressively rapid. During the period of exponential DNA increase at 37 °C, the rate of elongation was 749 nucleotides per second.
After DNA replication is complete, the cell must physically
separate the two copies of the genome and divide into two distinct
membrane-bound cells. In prokaryotes (bacteria and archaea) this usually occurs via a relatively simple process called binary fission, in which each circular genome attaches to the cell membrane and is separated into the daughter cells as the membrane invaginates to split the cytoplasm into two membrane-bound portions. Binary fission is extremely fast compared to the rates of cell division in eukaryotes. Eukaryotic cell division is a more complex process known as the cell cycle; DNA replication occurs during a phase of this cycle known as S phase, whereas the process of segregating chromosomes and splitting the cytoplasm occurs during M phase.
Molecular inheritance
The
duplication and transmission of genetic material from one generation of
cells to the next is the basis for molecular inheritance and the link
between the classical and molecular pictures of genes. Organisms inherit
the characteristics of their parents because the cells of the offspring
contain copies of the genes in their parents' cells. In asexually reproducing organisms, the offspring will be a genetic copy or clone of the parent organism. In sexually reproducing organisms, a specialized form of cell division called meiosis produces cells called gametes or germ cells that are haploid, or contain only one copy of each gene. The gametes produced by females are called eggs or ova, and those produced by males are called sperm. Two gametes fuse to form a diploidfertilized egg, a single cell that has two sets of genes, with one copy of each gene from the mother and one from the father.
During the process of meiotic cell division, an event called genetic recombination or crossing-over can sometimes occur, in which a length of DNA on one chromatid
is swapped with a length of DNA on the corresponding homologous
non-sister chromatid. This can result in reassortment of otherwise
linked alleles.
The Mendelian principle of independent assortment asserts that each of a
parent's two genes for each trait will sort independently into gametes;
which allele an organism inherits for one trait is unrelated to which
allele it inherits for another trait. This is in fact only true for
genes that do not reside on the same chromosome or are located very far
from one another on the same chromosome. The closer two genes lie on the
same chromosome, the more closely they will be associated in gametes
and the more often they will appear together (known as genetic linkage).
Genes that are very close are essentially never separated because it is
extremely unlikely that a crossover point will occur between them.
DNA replication is for the most part extremely accurate, however errors (mutations) do occur. The error rate in eukaryoticcells can be as low as 10−8 per nucleotide per replication, whereas for some RNA viruses it can be as high as 10−3. This means that each generation, each human genome accumulates 1–2 new mutations. Small mutations can be caused by DNA replication and the aftermath of DNA damage and include point mutations in which a single base is altered and frameshift mutations in which a single base is inserted or deleted. Either of these mutations can change the gene by missense (change a codon to encode a different amino acid) or nonsense (a premature stop codon). Larger mutations can be caused by errors in recombination to cause chromosomal abnormalities including the duplication,
deletion, rearrangement or inversion of large sections of a chromosome.
Additionally, DNA repair mechanisms can introduce mutational errors
when repairing physical damage to the molecule. The repair, even with
mutation, is more important to survival than restoring an exact copy,
for example when repairing double-strand breaks.
When multiple different alleles for a gene are present in a species's population it is called polymorphic. Most different alleles are functionally equivalent, however some alleles can give rise to different phenotypic traits. A gene's most common allele is called the wild type, and rare alleles are called mutants. The genetic variation in relative frequencies of different alleles in a population is due to both natural selection and genetic drift. The wild-type allele is not necessarily the ancestor of less common alleles, nor is it necessarily fitter.
Most mutations within genes are neutral, having no effect on the organism's phenotype (silent mutations). Some mutations do not change the amino acid sequence because multiple codons encode the same amino acid (synonymous mutations).
Other mutations can be neutral if they lead to amino acid sequence
changes, but the protein still functions similarly with the new amino
acid (e.g. conservative mutations). Many mutations, however, are deleterious or even lethal,
and are removed from populations by natural selection. Genetic
disorders are the result of deleterious mutations and can be due to
spontaneous mutation in the affected individual, or can be inherited.
Finally, a small fraction of mutations are beneficial, improving the organism's fitness and are extremely important for evolution, since their directional selection leads to adaptive evolution.
Sequence homology
A sequence alignment, produced by ClustalO, of mammalian histone proteins
Genes with a most recent common ancestor, and thus a shared evolutionary ancestry, are known as homologs.
These genes appear either from gene duplication within an organism's
genome, where they are known as paralogous genes, or are the result of
divergence of the genes after a speciation event, where they are known as orthologous genes,
and often perform the same or similar functions in related organisms.
It is often assumed that the functions of orthologous genes are more
similar than those of paralogous genes, although the difference is
minimal.
The relationship between genes can be measured by comparing the sequence alignment of their DNA. The degree of sequence similarity between homologous genes is called conserved sequence. Most changes to a gene's sequence do not affect its function and so genes accumulate mutations over time by neutral molecular evolution. Additionally, any selection on a gene will cause its sequence to diverge at a different rate. Genes under stabilizing selection are constrained and so change more slowly whereas genes under directional selection change sequence more rapidly. The sequence differences between genes can be used for phylogenetic analyses to study how those genes have evolved and how the organisms they come from are related.
Origins of new genes
Evolutionary fate of duplicate genes.
The most common source of new genes in eukaryotic lineages is gene duplication, which creates copy number variation of an existing gene in the genome. The resulting genes (paralogs) may then diverge in sequence and in function. Sets of genes formed in this way compose a gene family. Gene duplications and losses within a family are common and represent a major source of evolutionary biodiversity.
Sometimes, gene duplication may result in a nonfunctional copy of a
gene, or a functional copy may be subject to mutations that result in
loss of function; such nonfunctional genes are called pseudogenes.
"Orphan" genes,
whose sequence shows no similarity to existing genes, are less common
than gene duplicates. The human genome contains an estimate 18 to 60 genes with no identifiable homologs outside humans. Orphan genes arise primarily from either de novo emergence from previously non-coding sequence, or gene duplication followed by such rapid sequence change that the original relationship becomes undetectable. De novo genes are typically shorter and simpler in structure than most eukaryotic genes, with few if any introns. Over long evolutionary time periods, de novo gene birth may be responsible for a significant fraction of taxonomically-restricted gene families.
Horizontal gene transfer refers to the transfer of genetic material through a mechanism other than reproduction. This mechanism is a common source of new genes in prokaryotes, sometimes thought to contribute more to genetic variation than gene duplication. It is a common means of spreading antibiotic resistance, virulence, and adaptive metabolic functions. Although horizontal gene transfer is rare in eukaryotes, likely examples have been identified of protist and alga genomes containing genes of bacterial origin.
Genome
The genome is the total genetic material of an organism and includes both the genes and non-coding sequences. Eukaryotic genes can be annotated using FINDER.
Number of genes
Depiction of numbers of genes for representative plants (green),
The genome size, and the number of genes it encodes varies widely between organisms. The smallest genomes occur in viruses, and viroids (which act as a single non-coding RNA gene). Conversely, plants can have extremely large genomes, with rice containing >46,000 protein-coding genes. The total number of protein-coding genes (the Earth's proteome) is estimated to be 5 million sequences.
Although the number of base-pairs of DNA in the human genome has
been known since the 1960s, the estimated number of genes has changed
over time as definitions of genes, and methods of detecting them have
been refined. Initial theoretical predictions of the number of human
genes were as high as 2,000,000. Early experimental measures indicated there to be 50,000–100,000 transcribed genes (expressed sequence tags). Subsequently, the sequencing in the Human Genome Project indicated that many of these transcripts were alternative variants of the same genes, and the total number of protein-coding genes was revised down to ~20,000 with 13 genes encoded on the mitochondrial genome. With the GENCODE annotation project, that estimate has continued to fall to 19,000. Of the human genome, only 1–2% consists of protein-coding sequences, with the remainder being 'noncoding' DNA such as introns, retrotransposons, and noncoding RNAs. Every multicellular organism has all its genes in each cell of its body but not every gene functions in every cell .
Essential genes are the set of genes thought to be critical for an organism's survival. This definition assumes the abundant availability of all relevant nutrients
and the absence of environmental stress. Only a small portion of an
organism's genes are essential. In bacteria, an estimated 250–400 genes
are essential for Escherichia coli and Bacillus subtilis, which is less than 10% of their genes. Half of these genes are orthologs in both organisms and are largely involved in protein synthesis. In the budding yeast Saccharomyces cerevisiae the number of essential genes is slightly higher, at 1000 genes (~20% of their genes).
Although the number is more difficult to measure in higher eukaryotes,
mice and humans are estimated to have around 2000 essential genes (~10%
of their genes). The synthetic organism, Syn 3,
has a minimal genome of 473 essential genes and quasi-essential genes
(necessary for fast growth), although 149 have unknown function.
Gene nomenclature has been established by the HUGO Gene Nomenclature Committee (HGNC), a committee of the Human Genome Organisation, for each known human gene in the form of an approved gene name and symbol (short-form abbreviation),
which can be accessed through a database maintained by HGNC. Symbols
are chosen to be unique, and each gene has only one symbol (although
approved symbols sometimes change). Symbols are preferably kept
consistent with other members of a gene family and with homologs in other species, particularly the mouse due to its role as a common model organism.
Genetic engineering
Comparison of conventional plant breeding with transgenic and cisgenic genetic modification.
Genetic engineering is the modification of an organism's genome through biotechnology. Since the 1970s, a variety of techniques have been developed to specifically add, remove and edit genes in an organism. Recently developed genome engineering techniques use engineered nucleaseenzymes to create targeted DNA repair in a chromosome to either disrupt or edit a gene when the break is repaired. The related term synthetic biology is sometimes used to refer to extensive genetic engineering of an organism.
Genetic engineering is now a routine research tool with model organisms. For example, genes are easily added to bacteria and lineages of knockout mice with a specific gene's function disrupted are used to investigate that gene's function. Many organisms have been genetically modified for applications in agriculture, industrial biotechnology, and medicine.
For multicellular organisms, typically the embryo is engineered which grows into the adult genetically modified organism. However, the genomes of cells in an adult organism can be edited using gene therapy techniques to treat genetic diseases.
