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The human genome is the genome of Homo sapiens, which is stored on 23 chromosome pairs. Twenty-two of these are autosomal chromosome pairs, while the remaining pair is sex-determining. The haploid human genome occupies a total of just over 3 billion DNA base pairs.The Human Genome Project (HGP) produced a reference sequence of the euchromatic human genome, which is used worldwide in biomedical sciences.

The haploid human genome contains ca. 23,000 protein-coding genes, far fewer than had been expected before its sequencing. 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 (controversially) "junk" DNA.

Features

Genes

There are estimated ca. 23,000 human protein-coding genes. The estimate of the number of human genes has been repeatedly revised down from initial predictions of 100,000 or more as genome sequence quality and gene finding methods have improved.

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, human cells make extensive use of alternative splicing to produce several different proteins from a single gene, and the human proteome is thought to be much larger than those of the aforementioned organisms. Besides, most human genes have multiple exons, and human introns are frequently much longer than the flanking exons.

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. 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.

Regulatory sequences

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.

Identification of regulatory sequences relies in part on evolutionary conservation. The evolutionary branch between the human and mouse, for example, occurred 70–90 million years ago. 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.

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 "junk" DNA. The compact DNA sequence of the puffer fish makes it much easier to locate the regulatory genes.

Other DNA

Protein-coding sequences (specifically, coding exons) comprise less than 1.5% of the human genome. 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:

Repeat elements



Transposons



Junk DNA

However, there is also a large amount of sequence that does not fall under any known classification. Much of this sequence may be an evolutionary artifact that serves no present-day purpose, and these regions are sometimes collectively referred to as "junk" DNA. There are, however, a variety of emerging indications that many sequences within are likely to function 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,"...a tiling array with 5-nucleotide resolution that mapped transcription activity along 10 human chromosomes revealed that an average of 10% of the genome (compared to the 1 to 2% represented by bona fide exons) corresponds to polyadenylated transcripts, of which more than half do not overlap with known gene locations. 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."...the proportion of small (50-100 bp) segments in the mammalian genome that is under (purifying) selection can be estimated to be about 5%. This proportion is much higher than can be explained by protein-coding sequences alone, implying that the genome contains many additional features (such as untranslated regions, regulatory elements, non-protein-coding genes, and chromosomal structural elements) under selection for biological function." 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.

Information content

The 3 billion base pairs of the haploid human genome correspond to an information content of about 750 megabytes. 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), and between 1.5 and 1.9 bits per base pair for each individual chromosome, except for the Y chromosome, which has an entropy rate below 0.9 bits per base pair.

Information content of the haploid human genome by chromosome:
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 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 in zipped

Human Genome Project file
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

(Liu, Venkatesh and Maley 2008)
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


Sequencing

DNA sequencing determines the order of the nucleotide bases in a genome.

Composite

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.

Personal

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.

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. 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.

Mapping

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.

Variation

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." 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. 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.

Variation

Most studies of human genetic variation have focused on single nucleotide polymorphisms , which are substitutions in individual bases along a chromosome. Most analyses estimate that SNPs occur on average somewhere between every 1 in 100 and 1 in 1,000 base pairs 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", 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. 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.

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. 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.

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.

Evolution

Comparative genomics studies of mammalian genomes suggest that approximately 5% of the human genome has been conserved by evolution since the divergence of those species approximately 200 million years ago, containing the vast majority of genes. 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 large, fraction of human genes seem to be shared among most known vertebrates.The chimpanzee genome is 95% identical to the human genome. 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."Human chromosome 2 resulted from a fusion of two ancestral chromosomes that remained separate in the chimpanzee lineage"

"Large-scale sequencing of the chimpanzee genome is now imminent."

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."Our findings suggest that the deterioration of the olfactory repertoire occurred concomitant with the acquisition of full trichromatic color vision in primates."

Mitochondrial genome

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 Siberiamarker 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.

Epigenome

A variety of features of the human genome that transcend its primary DNA sequence, such as chromatin packaging, histone modifications and DNA methylation, are important in regulating gene expression, genome replication and other cellular processes.These "epigenetic" features are thought to be involved in cancer and other abnormalities, and some may be heritable across generations.

See also



References

  1. More than 9,000,000 Unique Genes in Human Gut Bacterial Community: Estimating Gene Numbers Inside a Human Body, 27 Jun 2009
  2. Evolutionary Trajectories of Primate Genes Involved in HIV Pathogenesis, 2 September 2009
  3. [1]
  4. [2]
  5. Carroll, Sean B. et al. (May 2008). "Regulating Evolution", Scientific American, pp. 60–67.
  6. Summary
  7. Zhandong Liu, Santosh S Venkatesh and Carlo C Maley, Sequence space coverage, entropy of genomes and the potential to detect non-human DNA in human samples, BMC Genomics 2008, 9:509, doi:10.1186/1471-2164-9-509, fig. 6, using the Lempel-Ziv estimators of entropy rate.
  8. at Project Gutenberg[3], zipped plaintext file, includes header information
  9. http://www.nytimes.com/2008/03/04/health/research/04geno.html
  10. from Bill Clinton's 2000 State of the Union address
  11. Online Mendelian Inheritance in Man (OMIM)


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