The human (Homo sapiens) genome is stored on 23 chromosome pairs and in the small mitochondrial DNA. Twenty-two of the 23 chromosomes belong to autosomal chromosome pairs, while the remaining pair is sex determinative. The haploid human genome occupies a total of just over three billion DNA base pairs. The Human Genome Project (HGP) produced a reference sequence of the euchromatic human genome, which is used worldwide in the biomedical sciences.
The haploid human genome contains about 23,000 protein-coding genes, which are far fewer than had been expected before sequencing.[1][2] In fact, only about 1.5% of the genome codes for proteins, while the rest consists of non-coding RNA genes, regulatory sequences, introns, and noncoding DNA (once known as "junk DNA").[3]
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There are estimated to be between 20,000 and 25,000 human protein-coding genes. The estimate of the number of human genes has been repeatedly revised down as genome sequence quality and gene finding methods have improved. In the late 1960s, predictions estimated that human cells had as many as 2,000,000 genes.[5]
Surprisingly, the number of human genes seems to be less than a factor of two greater than that of many much simpler organisms, such as the roundworm and the fruit fly. However, a larger proportion of human genes are related to central nervous system and especially brain development.
Human genes are distributed unevenly across the chromosomes. Each chromosome contains various gene-rich and gene-poor regions, which seem to be correlated with chromosome bands and GC-content. The significance of these nonrandom patterns of gene density is not well understood.[6] In addition to protein coding genes, the human genome contains thousands of RNA genes, including tRNA, ribosomal RNA, microRNA, and other non-coding RNA genes.[7]
The human genome has many different regulatory sequences which are crucial to controlling gene expression. These are typically short sequences that appear near or within genes. A systematic understanding of these regulatory sequences and how they together act as a gene regulatory network is only beginning to emerge from computational, high-throughput expression and comparative genomics studies. Some types of non-coding DNA are genetic "switches" that do not encode proteins, but do regulate when and where genes are expressed.[8]
Identification of regulatory sequences relies in part on evolutionary conservation. The evolutionary branch between the primates and mouse, for example, occurred 70–90 million years ago.[9] So computer comparisons of gene sequences that identify conserved non-coding sequences will be an indication of their importance in duties such as gene regulation.[10]
Another comparative genomic approach to locating regulatory sequences in humans is the gene sequencing of the puffer fish. These vertebrates have essentially the same genes and regulatory gene sequences as humans, but with only one-eighth the noncoding DNA. The compact DNA sequence of the puffer fish makes it much easier to locate the regulatory genes.[11]
Protein-coding sequences (specifically, coding exons) comprise less than 1.5% of the human genome.[3] Aside from genes and known regulatory sequences, the human genome contains vast regions of DNA the function of which, if any, remains unknown. These regions in fact comprise the vast majority, by some estimates 97%, of the human genome size. Much of this is composed of:
Many DNA sequences that do not code for gene expression have important biological functions as indicated by comparative genomics studies that report some sequences of noncoding DNA that are highly conserved, sometimes on time-scales representing hundreds of millions of years, implying that these noncoding regions are under strong evolutionary pressure and positive selection.[12] These noncoding sequences were once referred to as "junk" DNA and there are many sequences that are likely to function, but in ways that are not fully understood. Recent experiments using microarrays have revealed that a substantial fraction of non-genic DNA is in fact transcribed into RNA,[13] which leads to the possibility that the resulting transcripts may have some unknown function. Also, the evolutionary conservation across the mammalian genomes of much more sequence than can be explained by protein-coding regions indicates that many, and perhaps most, functional elements in the genome remain unknown.[14] The investigation of the vast quantity of sequence information in the human genome whose function remains unknown is currently a major avenue of scientific inquiry.[15] Meanwhile, considering the global genome DNA information as a whole could provide new ways to understand a possible global level function of non coding DNA.[16]
The 2.9 billion[17][18] base pairs of the haploid human genome correspond to a maximum of about 725 megabytes of data, since every base pair can be coded by 2 bits. Since individual genomes vary by less than 1% from each other, they can be losslessly compressed to roughly 4 megabytes.[19]
The entropy rate of the genome differs significantly between coding and non-coding sequences. It is close to the maximum of 2 bits per base pair for the coding sequences (about 45 million base pairs), but less for the non-coding parts. It ranges between 1.5 and 1.9 bits per base pair for the individual chromosome, except for the Y-chromosome, which has an entropy rate below 0.9 bits per base pair.[20]
Information content of the haploid human genome by chromosome:
Haploid means we only count one of each chromosome pair. For this reason, the total information content for a woman (XX) is less than for a man (XY), where both the X and the Y are counted.
| total (XY) | total (XX) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | X | Y | |
| million base pairs (Mbp) | 3,080 | 3,022 | 247 | 243 | 199 | 191 | 181 | 171 | 159 | 146 | 140 | 135 | 134 | 132 | 114 | 106 | 100 | 89 | 79 | 76 | 63 | 62 | 47 | 50 | 155 | 58 |
| megabytes (raw data) | 770 | 756 | 61.8 | 60.7 | 49.9 | 47.8 | 45.2 | 42.7 | 39.7 | 36.6 | 35.1 | 33.9 | 33.6 | 33.1 | 28.5 | 26.6 | 25.1 | 22.2 | 19.7 | 19.0 | 16.0 | 15.6 | 11.7 | 12.4 | 38.7 | 14.4 |
| megabytes (zipped ASCII text) Human Genome Project file[21] |
827 | 819 | 65.1 | 68.2 | 57.4 | 52.3 | 51.3 | 48.8 | 45.3 | 38.6 | 33.9 | 39.1 | 39.8 | 38.8 | 28.8 | 26.5 | 22.9 | 22.5 | 22.7 | 22.2 | 16.4 | 18.9 | 10.4 | 10.4 | 38.6 | 8.0 |
| entropy rate in bits per base pair[20] | 1.70 | 1.71 | 1.82 | 1.80 | 1.82 | 1.82 | 1.83 | 1.82 | 1.81 | 1.83 | 1.59 | 1.83 | 1.84 | 1.59 | 1.56 | 1.53 | 1.66 | 1.82 | 1.87 | 1.58 | 1.86 | 1.82 | 1.62 | 1.83 | 1.80 | 0.84 |
DNA sequencing determines the order of the nucleotide bases in a genome.
The Human Genome Project and a parallel project by Celera Genomics each produced and published a haploid human genome sequence, both of which were a composite of the DNA sequence of several individuals.[22]
A personal genome sequence is a complete sequencing of the chemical base pairs that make up the DNA of a single person. Because medical treatments have different effects on different people because of genetic variations such as single-nucleotide polymorphisms (SNPs), the analysis of personal genomes may lead to personalized medical treatment based on individual genotypes.
The completion of the fifth such map was announced in December 2008. The genome mapped was that of a Korean researcher Seong-Jin Kim. Genome maps had previously been completed for Craig Venter of the U.S. in 2007, James Watson of the U.S. in April 2008, and Yang Huanming of China in November 2008 and Dan Stoicescu in January 2008.[23][24][25]
Personal genomes had not been sequenced in the Human Genome Project to protect the identity of volunteers who provided DNA samples. That sequence was derived from the DNA of several volunteers from a diverse population.[26] Another distinction is that the HGP sequence is haploid, however, the sequence maps for Venter and Watson for example are diploid, representing both sets of chromosomes.
Kim’s genome had 1.58 million SNPs that had never been reported before and indicates that six out of 10,000 DNA bases are unique to Koreans. Kim's sequence map can be used to assist in building a standard Korean genome, which can then be used to compare the genomes of other Korean individuals for personalized medical treatments.
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.[27][28]
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."[29] 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.[30][31] 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.
Most studies of human genetic variation have focused on single-nucleotide polymorphisms (SNPs), which are substitutions in individual bases along a chromosome. Most analyses estimate that SNPs occur 1 in 1000 base pairs, on average, in the euchromatic human genome, although they do not occur at a uniform density. Thus follows the popular statement that "we are all, regardless of race, genetically 99.9% the same",[32] although this would be somewhat qualified by most geneticists. For example, a much larger fraction of the genome is now thought to be involved in copy number variation.[33] A large-scale collaborative effort to catalog SNP variations in the human genome is being undertaken by the International HapMap Project.
The genomic loci and length of certain types of small repetitive sequences are highly variable from person to person, which is the basis of DNA fingerprinting and DNA paternity testing technologies. The heterochromatic portions of the human genome, which total several hundred million base pairs, are also thought to be quite variable within the human population (they are so repetitive and so long that they cannot be accurately sequenced with current technology). These regions contain few genes, and it is unclear whether any significant phenotypic effect results from typical variation in repeats or heterochromatin.
Most gross genomic mutations in gamete germ cells probably result in inviable embryos; however, a number of human diseases are related to large-scale genomic abnormalities. Down syndrome, Turner Syndrome, and a number of other diseases result from nondisjunction of entire chromosomes. Cancer cells frequently have aneuploidy of chromosomes and chromosome arms, although a cause and effect relationship between aneuploidy and cancer has not been established.
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. Disease-causing mutations in specific genes are usually severe in terms of gene function, and are fortunately rare, thus genetic disorders are similarly individually rare. However, since there are many genes that can vary to cause genetic disorders, in aggregate they comprise 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.[34]
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 it will be inherited, and how to avoid or ameliorate it in their offspring.
As noted above, 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.
Comparative genomics studies of mammalian genomes suggest that approximately 5% of the human genome has been conserved by evolution since the divergence of extant lineages approximately 200 million years ago, containing the vast majority of genes.[14][15] Intriguingly, since genes and known regulatory sequences probably comprise less than 2% of the genome, this suggests that there may be more unknown functional sequence than known functional sequence. A smaller, yet substantial, fraction of human genes seem to be shared among most known vertebrates. The published chimpanzee genome differs from that of the human genome by 1.23% in direct sequence comparisons.[35] Around 20% of this figure is accounted for by variation within each species, leaving only ~1.06% consistent sequence divergence between humans and chimps at shared genes.[36] This nucleotide by nucleotide difference is dwarfed, however, by the portion of each genome that is not shared, including around 6% of functional genes that are unique to either humans or chimps.[37] 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 ortholog by only two amino acid substitutions; nearly one third of human genes have exactly the same protein translation as their chimpanzee orthologs. A major difference between the two genomes is human chromosome 2, which is equivalent to a fusion product of chimpanzee chromosomes 12 and 13[38] (later renamed to chromosomes 2A and 2B, respectively).
Humans have undergone an extraordinary loss of olfactory receptor genes during our recent evolution, which explains our relatively crude sense of smell compared to most other mammals. Evolutionary evidence suggests that the emergence of color vision in humans and several other primate species has diminished the need for the sense of smell.[39]
The human mitochondrial genome, while usually not included when referring to the "human genome", 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, Mitochondrial DNA (mtDNA) has a more rapid rate of variation than nuclear DNA. This 20-fold increase in the mutation rate allows mtDNA to be used for more accurate tracing of maternal ancestry. Studies of mtDNA in populations have allowed ancient migration paths to be traced, such as the migration of Native Americans from Siberia or Polynesians from southeastern Asia. 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.[40]
Epigenetics are 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.[41][42]
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