Human genome
The human genome is a complete set of
Although the sequence of the human genome has been completely determined by DNA sequencing in 2022, it is not yet fully understood. Most, but not all, genes have been identified by a combination of high throughput experimental and bioinformatics approaches, yet much work still needs to be done to further elucidate the biological functions of their protein and RNA products (in particular, annotation of the complete CHM13v2.0 sequence is still ongoing[2]).
Size of the human genome
In 2003 scientists reported the sequencing of 85% of the entire human genome, but as of 2020 at least 8% was still missing.[
The current version of the standard reference genome is called GRCh38.p14 (July 2023). It consists of 22 autosomes plus one copy of the X chromosome and one copy of the Y chromosome. It contains approximately 3.1 billion base pairs (3.1 Gb or 3.1 x 109 bp).[6] This represents the size of a composite genome based on data from multiple individuals but it is a good indication of the typical amount of DNA in a haploid set of chromosomes. Most human cells are diploid so they contain twice as much DNA.
In 2023, a draft human pangenome reference was published.[7] It is based on 47 genomes from persons of varied ethnicity.[7] Plans are underway for an improved reference capturing still more biodiversity from a still wider sample.[7]
While there are significant differences among the genomes of human individuals (on the order of 0.1% due to
Molecular organization and gene content
The total length of the human reference genome does not represent the sequence of any specific individual. The genome is organized into 22 paired chromosomes, termed autosomes, plus the 23rd pair of sex chromosomes (XX) in the female and (XY) in the male. These chromosomes are all large linear DNA molecules contained within the cell nucleus. The current version of the human reference genome includes one copy of each of the autosomes plus one copy of the two sex chromosomes (X and Y). The total amount of DNA is 3.1 billion base pairs (3.1 Gb).[12]
Protein-coding genes
Protein-coding sequences represent the most widely studied and best understood component of the human genome. These sequences ultimately lead to the production of all human proteins, although several biological processes (e.g. DNA rearrangements and alternative pre-mRNA splicing) can lead to the production of many more unique proteins than the number of protein-coding genes.
The human genome contains somewhere between 19,000 and 20,000 protein-coding genes. [13][14][15][16] These genes contain an average of 10 introns and the average size of an intron is about 6 kb (6,000 bp).[17] This means that the average size of a protein-coding gene is about 62 kb and these genes take up about 40% of the genome.[18]
Exon sequences consist of coding DNA and untranslated regions (UTRs) at either end of the mature mRNA. The total amount of coding DNA is about 1-2% of the genome.[19][17]
Many people divide the genome into coding and non-coding DNA based on the idea that coding DNA is the most important functional component the genome. About 98-99% of the human genome is non-coding DNA.
Non-coding genes
Noncoding RNA molecules play many essential roles in cells, especially in the many reactions of
Many ncRNAs are critical elements in gene regulation and expression. Noncoding RNA also contributes to epigenetics, transcription, RNA splicing, and the translational machinery. The role of RNA in genetic regulation and disease offers a new potential level of unexplored genomic complexity.[25]
Pseudogenes
Pseudogenes are inactive copies of protein-coding genes, often generated by gene duplication, that have become nonfunctional through the accumulation of inactivating mutations. The number of pseudogenes in the human genome is on the order of 13,000,[26] and in some chromosomes is nearly the same as the number of functional protein-coding genes. Gene duplication is a major mechanism through which new genetic material is generated during molecular evolution.
For example, the olfactory receptor gene family is one of the best-documented examples of pseudogenes in the human genome. More than 60 percent of the genes in this family are non-functional pseudogenes in humans. By comparison, only 20 percent of genes in the mouse olfactory receptor gene family are pseudogenes. Research suggests that this is a species-specific characteristic, as the most closely related primates all have proportionally fewer pseudogenes. This genetic discovery helps to explain the less acute sense of smell in humans relative to other mammals.[27]
Regulatory DNA sequences
The human genome has many different
Regulatory sequences have been known since the late 1960s.
Other genomes have been sequenced with the same intention of aiding conservation-guided methods, for exampled the
As of 2012, the efforts have shifted toward finding interactions between DNA and regulatory proteins by the technique
Repetitive DNA sequences
About 8% of the human genome consists of tandem DNA arrays or tandem repeats, low complexity repeat sequences that have multiple adjacent copies (e.g. "CAGCAGCAG...").
Repeated sequences of fewer than ten nucleotides (e.g. the dinucleotide repeat (AC)n) are termed microsatellite sequences. Among the microsatellite sequences, trinucleotide repeats are of particular importance, as sometimes occur within
Tandem repeats of longer sequences (arrays of repeated sequences 10–60 nucleotides long) are termed minisatellites.[43]
Mobile elements within the human genome can be classified into
(2.9% of total genome).Junk DNA
There is no consensus on what constitutes a "functional" element in the genome since geneticists, evolutionary biologists, and molecular biologists employ different definitions and methods.[48][49] Due to the ambiguity in the terminology, different schools of thought have emerged.[50] In evolutionary definitions, "functional" DNA, whether it is coding or non-coding, contributes to the fitness of the organism, and therefore is maintained by negative evolutionary pressure whereas "non-functional" DNA has no benefit to the organism and therefore is under neutral selective pressure. This type of DNA has been described as junk DNA[51][52] In genetic definitions, "functional" DNA is related to how DNA segments manifest by phenotype and "nonfunctional" is related to loss-of-function effects on the organism.[48] In biochemical definitions, "functional" DNA relates to DNA sequences that specify molecular products (e.g. noncoding RNAs) and biochemical activities with mechanistic roles in gene or genome regulation (i.e. DNA sequences that impact cellular level activity such as cell type, condition, and molecular processes).[53][48] There is no consensus in the literature on the amount of functional DNA since, depending on how "function" is understood, ranges have been estimated from up to 90% of the human genome is likely nonfunctional DNA (junk DNA)[54] to up to 80% of the genome is likely functional.[55] It is also possible that junk DNA may acquire a function in the future and therefore may play a role in evolution,[56] but this is likely to occur only very rarely.[51] Finally DNA that is deliterious to the organism and is under negative selective pressure is called garbage DNA.[52]
Sequencing
The first human
These data are used worldwide in
By 2018, the total number of genes had been raised to at least 46,831,
In 2022 the Telomere-to-Telomere (T2T) consortium reported the complete sequence of a human female genome,
Although the 'completion' of the human genome project was announced in 2001,[68] there remained hundreds of gaps, with about 5–10% of the total sequence remaining undetermined. The missing genetic information was mostly in repetitive heterochromatic regions and near the centromeres and telomeres, but also some gene-encoding euchromatic regions.[69] There remained 160 euchromatic gaps in 2015 when the sequences spanning another 50 formerly unsequenced regions were determined.[70] Only in 2020 was the first truly complete telomere-to-telomere sequence of a human chromosome determined, namely of the X chromosome.[71] The first complete telomere-to-telomere sequence of a human autosomal chromosome, chromosome 8, followed a year later.[72] The complete human genome (without Y chromosome) was published in 2021, while with Y chromosome in January 2022.[4][3][73]
In 2023, a draft human pangenome reference was published.[7] It is based on 47 genomes from persons of varied ethnicity.[7] Plans are underway for an improved reference capturing still more biodiversity from a still wider sample.[7]
Genomic variation in humans
Human reference genome
With the exception of identical twins, all humans show significant variation in genomic DNA sequences. The human reference genome (HRG) is used as a standard sequence reference.
There are several important points concerning the human reference genome:
- The HRG is a haploid sequence. Each chromosome is represented once.
- The HRG is a composite sequence, and does not correspond to any actual human individual.
- The HRG is periodically updated to correct errors, ambiguities, and unknown "gaps".
- The HRG in no way represents an "ideal" or "perfect" human individual. It is simply a standardized representation or model that is used for comparative purposes.
The Genome Reference Consortium is responsible for updating the HRG. Version 38 was released in December 2013.[74]
Measuring human genetic variation
Most studies of human genetic variation have focused on
The genomic loci and length of certain types of small
Most gross genomic mutations in
Mapping human genomic variation
Whereas a genome sequence lists the order of every DNA base in a genome, a genome map identifies the landmarks. A genome map is less detailed than a genome sequence and aids in navigating around the genome.[77][78]
An example of a variation map is the HapMap being developed by the International HapMap Project. The HapMap is a haplotype map of the human genome, "which will describe the common patterns of human DNA sequence variation."[79] It catalogs the patterns of small-scale variations in the genome that involve single DNA letters, or bases.
Researchers published the first sequence-based map of large-scale structural variation across the human genome in the journal Nature in May 2008.[80][81] Large-scale structural variations are differences in the genome among people that range from a few thousand to a few million DNA bases; some are gains or losses of stretches of genome sequence and others appear as re-arrangements of stretches of sequence. These variations include differences in the number of copies individuals have of a particular gene, deletions, translocations and inversions.
Structural variation
Structural variation refers to genetic variants that affect larger segments of the human genome, as opposed to point mutations. Often, structural variants (SVs) are defined as variants of 50 base pairs (bp) or greater, such as deletions, duplications, insertions, inversions and other rearrangements. About 90% of structural variants are noncoding deletions but most individuals have more than a thousand such deletions; the size of deletions ranges from dozens of base pairs to tens of thousands of bp.[82] On average, individuals carry ~3 rare structural variants that alter coding regions, e.g. delete exons. About 2% of individuals carry ultra-rare megabase-scale structural variants, especially rearrangements. That is, millions of base pairs may be inverted within a chromosome; ultra-rare means that they are only found in individuals or their family members and thus have arisen very recently.[82]
SNP frequency across the human genome
Single-nucleotide polymorphisms (SNPs) do not occur homogeneously across the human genome. In fact, there is enormous diversity in
Changes in non-coding sequence and synonymous changes in coding sequence are generally more common than non-synonymous changes, reflecting greater selective pressure reducing diversity at positions dictating amino acid identity. Transitional changes are more common than transversions, with CpG dinucleotides showing the highest mutation rate, presumably due to deamination.[citation needed
Personal genomes
A personal genome sequence is a (nearly) complete
The first personal genome sequence to be determined was that of
The sequencing of individual genomes further unveiled levels of genetic complexity that had not been appreciated before. Personal genomics helped reveal the significant level of diversity in the human genome attributed not only to SNPs but structural variations as well. However, the application of such knowledge to the treatment of disease and in the medical field is only in its very beginnings.[98] Exome sequencing has become increasingly popular as a tool to aid in diagnosis of genetic disease because the exome contributes only 1% of the genomic sequence but accounts for roughly 85% of mutations that contribute significantly to disease.[99]
Human knockouts
In humans,
Populations with high rates of consanguinity, such as countries with high rates of first-cousin marriages, display the highest frequencies of homozygous gene knockouts. Such populations include Pakistan, Iceland, and Amish populations. These populations with a high level of parental-relatedness have been subjects of human knock out research which has helped to determine the function of specific genes in humans. By distinguishing specific knockouts, researchers are able to use phenotypic analyses of these individuals to help characterize the gene that has been knocked out.
Knockouts in specific genes can cause genetic diseases, potentially have beneficial effects, or even result in no phenotypic effect at all. However, determining a knockout's phenotypic effect and in humans can be challenging. Challenges to characterizing and clinically interpreting knockouts include difficulty calling of DNA variants, determining disruption of protein function (annotation), and considering the amount of influence
One major study that investigated human knockouts is the Pakistan Risk of Myocardial Infarction study. It was found that individuals possessing a heterozygous loss-of-function gene knockout for the
Human genetic disorders
Most aspects of human biology involve both genetic (inherited) and non-genetic (environmental) factors. Some inherited variation influences aspects of our biology that are not medical in nature (height, eye color, ability to taste or smell certain compounds, etc.). Moreover, some genetic disorders only cause disease in combination with the appropriate environmental factors (such as diet). With these caveats, genetic disorders may be described as clinically defined diseases caused by genomic DNA sequence variation. In the most straightforward cases, the disorder can be associated with variation in a single gene. For example, cystic fibrosis is caused by mutations in the CFTR gene and is the most common recessive disorder in caucasian populations with over 1,300 different mutations known.[102]
Disease-causing mutations in specific genes are usually severe in terms of gene function and are rare, thus genetic disorders are similarly individually rare. However, since there are many genes that can vary to cause genetic disorders, in aggregate they constitute a significant component of known medical conditions, especially in pediatric medicine. Molecularly characterized genetic disorders are those for which the underlying causal gene has been identified. Currently there are approximately 2,200 such disorders annotated in the OMIM database.[102]
Studies of genetic disorders are often performed by means of family-based studies. In some instances, population based approaches are employed, particularly in the case of so-called founder populations such as those in Finland, French-Canada, Utah, Sardinia, etc. Diagnosis and treatment of genetic disorders are usually performed by a geneticist-physician trained in clinical/medical genetics. The results of the Human Genome Project are likely to provide increased availability of genetic testing for gene-related disorders, and eventually improved treatment. Parents can be screened for hereditary conditions and counselled on the consequences, the probability of inheritance, and how to avoid or ameliorate it in their offspring.
There are many different kinds of DNA sequence variation, ranging from complete extra or missing chromosomes down to single nucleotide changes. It is generally presumed that much naturally occurring genetic variation in human populations is phenotypically neutral, i.e., has little or no detectable effect on the physiology of the individual (although there may be fractional differences in fitness defined over evolutionary time frames). Genetic disorders can be caused by any or all known types of sequence variation. To molecularly characterize a new genetic disorder, it is necessary to establish a causal link between a particular genomic sequence variant and the clinical disease under investigation. Such studies constitute the realm of human molecular genetics.
With the advent of the Human Genome and International HapMap Project, it has become feasible to explore subtle genetic influences on many common disease conditions such as diabetes, asthma, migraine, schizophrenia, etc. Although some causal links have been made between genomic sequence variants in particular genes and some of these diseases, often with much publicity in the general media, these are usually not considered to be genetic disorders per se as their causes are complex, involving many different genetic and environmental factors. Thus there may be disagreement in particular cases whether a specific medical condition should be termed a genetic disorder.
Additional genetic disorders of mention are Kallman syndrome and Pfeiffer syndrome (gene FGFR1), Fuchs corneal dystrophy (gene TCF4), Hirschsprung's disease (genes RET and FECH), Bardet-Biedl syndrome 1 (genes CCDC28B and BBS1), Bardet-Biedl syndrome 10 (gene BBS10), and facioscapulohumeral muscular dystrophy type 2 (genes D4Z4 and SMCHD1).[103]
Genome sequencing is now able to narrow the genome down to specific locations to more accurately find mutations that will result in a genetic disorder.
Disorder | Prevalence | Chromosome or gene involved |
---|---|---|
Chromosomal conditions | ||
Down syndrome | 1:600 | Chromosome 21 |
Klinefelter syndrome | 1:500–1000 males | Additional X chromosome |
Turner syndrome | 1:2000 females | Loss of X chromosome |
Sickle cell anemia
|
1 in 50 births in parts of Africa; rarer elsewhere | β-globin (on chromosome 11)
|
Bloom syndrome | 1:48000 Ashkenazi Jews | BLM |
Cancers | ||
Breast/Ovarian cancer (susceptibility) | ~5% of cases of these cancer types | BRCA1, BRCA2 |
FAP (hereditary nonpolyposis coli) | 1:3500 | APC |
Lynch syndrome
|
5–10% of all cases of bowel cancer | MLH1, MSH2, MSH6, PMS2 |
Fanconi anemia | 1:130000 births | FANCC |
Neurological conditions | ||
Huntington disease
|
1:20000 | Huntingtin |
Alzheimer disease - early onset
|
1:2500 | |
Tay-Sachs | 1:3600 births in Ashkenazi Jews | HEXA gene (on chromosome 15) |
Canavan disease | 2.5% Eastern European Jewish ancestry | ASPA gene (on chromosome 17) |
Familial dysautonomia | 600 known cases worldwide since discovery | IKBKAP gene (on chromosome 9) |
Fragile X syndrome | 1.4:10000 in males, 0.9:10000 in females | FMR1 gene (on X chromosome) |
Mucolipidosis type IV | 1:90 to 1:100 in Ashkenazi Jews | MCOLN1 |
Other conditions | ||
Cystic fibrosis | 1:2500 | CFTR |
Duchenne muscular dystrophy | 1:3500 boys | Dystrophin |
Becker muscular dystrophy | 1.5–6:100000 males | DMD |
Beta thalassemia | 1:100000 | HBB |
Congenital adrenal hyperplasia | 1:280 in Native Americans and Yupik Eskimos
1:15000 in American Caucasians |
CYP21A2 |
Glycogen storage disease type I | 1:100000 births in America | G6PC |
Maple syrup urine disease | 1:180000 in the U.S.
1:176 in Mennonite/Amish communities 1:250000 in Austria |
BCKDHA, BCKDHB, DBT, DLD |
Niemann–Pick disease, SMPD1-associated | 1,200 cases worldwide | SMPD1 |
Usher syndrome | 1:23000 in the U.S.
1:28000 in Norway 1:12500 in Germany |
CDH23, CLRN1, DFNB31, GPR98, MYO7A, PCDH15, USH1C, USH1G, USH2A |
Evolution
million years ago ) |
In other words, the considerable observable differences between humans and chimps may be due as much or more to genome level variation in the number, function and expression of genes rather than DNA sequence changes in shared genes. Indeed, even within humans, there has been found to be a previously unappreciated amount of copy number variation (CNV) which can make up as much as 5–15% of the human genome. In other words, between humans, there could be +/- 500,000,000 base pairs of DNA, some being active genes, others inactivated, or active at different levels. The full significance of this finding remains to be seen. On average, a typical human protein-coding gene differs from its chimpanzee
Humans have undergone an extraordinary loss of
In September 2016, scientists reported that, based on human DNA genetic studies, all
Mitochondrial DNA
The human mitochondrial DNA is of tremendous interest to geneticists, since it undoubtedly plays a role in mitochondrial disease. It also sheds light on human evolution; for example, analysis of variation in the human mitochondrial genome has led to the postulation of a recent common ancestor for all humans on the maternal line of descent (see Mitochondrial Eve).
Due to the lack of a system for checking for copying errors,[115] mitochondrial DNA (mtDNA) has a more rapid rate of variation than nuclear DNA. This 20-fold higher mutation rate allows mtDNA to be used for more accurate tracing of maternal ancestry.[citation needed] Studies of mtDNA in populations have allowed ancient migration paths to be traced, such as the migration of Native Americans from Siberia[116] or Polynesians from southeastern Asia.[citation needed] It has also been used to show that there is no trace of Neanderthal DNA in the European gene mixture inherited through purely maternal lineage.[117] Due to the restrictive all or none manner of mtDNA inheritance, this result (no trace of Neanderthal mtDNA) would be likely unless there were a large percentage of Neanderthal ancestry, or there was strong positive selection for that mtDNA. For example, going back 5 generations, only 1 of a person's 32 ancestors contributed to that person's mtDNA, so if one of these 32 was pure Neanderthal an expected ~3% of that person's autosomal DNA would be of Neanderthal origin, yet they would have a ~97% chance of having no trace of Neanderthal mtDNA.[citation needed]
Epigenome
Epigenetics describes a variety of features of the human genome that transcend its primary DNA sequence, such as chromatin packaging, histone modifications and DNA methylation, and which are important in regulating gene expression, genome replication and other cellular processes. Epigenetic markers strengthen and weaken transcription of certain genes but do not affect the actual sequence of DNA nucleotides. DNA methylation is a major form of epigenetic control over gene expression and one of the most highly studied topics in epigenetics. During development, the human DNA methylation profile experiences dramatic changes. In early germ line cells, the genome has very low methylation levels. These low levels generally describe active genes. As development progresses, parental imprinting tags lead to increased methylation activity.[118][119]
Epigenetic patterns can be identified between tissues within an individual as well as between individuals themselves. Identical genes that have differences only in their epigenetic state are called epialleles. Epialleles can be placed into three categories: those directly determined by an individual's genotype, those influenced by genotype, and those entirely independent of genotype. The epigenome is also influenced significantly by environmental factors. Diet, toxins, and hormones impact the epigenetic state. Studies in dietary manipulation have demonstrated that methyl-deficient diets are associated with hypomethylation of the epigenome. Such studies establish epigenetics as an important interface between the environment and the genome.[120]
See also
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External links
- Annotated (version 110) genome viewer of T2T-CHM13 v2.0
- Complete human genome T2T-CHM13 v2.0 (no gaps)
- Ensembl The EnsemblGenome Browser Project
- National Library of Medicine Genome Data Viewer (GDV)
- UCSC Genome Browser using T2T-CHM13 v2.0
- Uniprot: per chromosome gene list
- Human Genome Project
- The National Human Genome Research Institute
- The National Office of Public Health Genomics
- Simple Human Genome viewer