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A graphical representation of the normal human karyotype.

The human genome is the genome of Homo sapiens, which has 24 distinct chromosomes (22 autosomal + X + Y) with a total of approximately 3 billion DNA base pairs containing an estimated 20,000–25,000 genes. ^[1] The Human Genome Project has produced a reference sequence of the euchromatic human genome, which is used worldwide in biomedical sciences. The human genome had fewer genes than expected, with only about 1.5% coding for proteins, and the rest comprised by RNA genes, regulatory sequences, introns and controversially so-called junk DNA.^[2]

The human genome is composed of 23 pairs of chromosomes (46 in total), each of which contain hundreds of genes separated by intergenic regions. Intergenic regions may contain regulatory sequences and non-coding DNA.

There are 24 distinct human chromosomes: 22 autosomal chromosomes, plus the sex-determining X and Y chromosomes. Chromosomes 1–22 are numbered roughly in order of decreasing size. Somatic cells usually have 23 chromosome pairs: one copy of chromosomes 1–22 from each parent, plus an X chromosome from the mother, and either an X or Y chromosome from the father, for a total of 46.

There are an estimated 20,000–25,000 human protein-coding genes ^[1]

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.

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.

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.

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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.^[3] 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. ^[4]

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.^[5]

Protein-coding sequences (specifically, coding exons) comprise less than 1.5% of the human genome.^[2] 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 comprised of:

• Tandem repeats
  • Satellite DNA
  • Minisatellite
  • Microsatellite
• Interspersed repeats
  • SINEs
  • LINEs

• Retrotransposons
  • LTR
    • Ty1-copia
    • Ty3-gypsy
  • Non-LTR
    • SINEs
    • LINEs
• DNA Transposons

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,^[6] 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.^[7] 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. ^[8]

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 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", ^[9] 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. ^[10] 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 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.

For more details on this topic, see Genetic disorder.

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These conditions are caused by abnormal expression of one or more genes that matches a clinical phenotype. The disorder may be caused by a gene mutation, an abnormal number of chromosomes, or triplet expansion repeat mutations. Defective genes can be inherited from the parents, in which case it is known as a hereditary disease. There are around 4,000 known genetic disorders,^{[citation needed]} with the most common being cystic fibrosis.

Studies of genetic disorders is often performed by means of population genetics. Treatment is performed by a geneticist-physician trained in clinical 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.

One major gross effect on human phenotypes derives from gene dosage, whose effects play a role in disorders caused by duplication, omission, or disruption of chromosomes. For example, those afflicted with Down syndrome, or trisomy 21, experience high rates of Alzheimer's disease, an effect thought to be related to the overexpression of the Alzheimer's-related amyloid precursor protein whose gene is located on chromosome 21.^[11] By contrast, Down's syndrome sufferers experience lower rates of breast cancer, possibly due to the overexpression of a tumor-suppressor gene.^[12]

See also: Human evolution and Chimpanzee Genome Project

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.^[7][8] 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, but 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.^[13]

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.^[14]

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. ^[15]

See also: Epigenetics

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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.^[16][17] These "epigenetic" features are thought to be involved in cancer and other abnormalities, and some may be heritable across generations.

• Lindblad-Toh K, et al. (2005). "Genome sequence, comparative analysis and haplotype structure of the domestic dog.". Nature 438 (7069): 803-19. PMID 16341006. [5]

• The National Human Genome Research Institute
• Ensembl The Ensembl Genome Browser Project
• National Library of Medicine human genome viewer
• UCSC Genome Browser.
• Human Genome Project.
• Sabancı University School of Languages Podcasts What makes us different from chimpanzees? by Andrew Berry (MP3 file)
• The National Office of Public Health Genomics
• New findings: established views about human genome challenged [6] [7] [8]