This chapter is from the book
This chapter is from the book
This chapter is from the book
How many disease genes are there?
In 1957, Victor McKusick was appointed director of the new Moore Clinic for Chronic Diseases at Johns Hopkins University and head of the newly established Division of Medical Genetics at its medical school.43 He had come into human genetics via his research on disorders affecting connective tissue, including Marfan's syndrome. Marfan's sufferers typically have long slender limbs and are often taller than normal. The most serious conditions associated with the disease primarily involve the cardiovascular system, as there may be leakage through the mitral or aortic valves that control blood flow through the heart. McKusick noticed that Marfan's syndrome exhibited a familial pattern of occurrence and, indeed, we know today that a dominant genetic mutation is involved. The Marfan's pedigree sparked McKusick's interest and he began to specialize in human clinical genetics.
In 1966, he published his first catalog of all known genes and genetic disorders, Mendelian Inheritance in Man (MIM). The 12th edition of his catalog was published in 1998. Meanwhile, a free online version (OMIM) first became available in 1987. It is continuously updated. The database is linked with the National Center for Biotechnology Information and the National Library of Medicine for distribution. In the 1980s, only a few genes were being found each year. By 2000, the number of genes discovered each year was approaching 175. More than 6,000 single gene disorders are currently known,44 meaning that mutations in somewhere around 24% of the approximately 25,000 human genes found so far can cause genetic disease. Because of the broad interest in disease genes as well as the availability of increasingly sophisticated technical and statistical tools, the rate of disease gene discovery has expanded rapidly. Whether or not it plateaus at some point remains to be seen.
It was originally thought that the human genome might contain as many as 100,000 genes. Once the Human Genome Project was completed in 2003 and a few further revisions were made, this number dropped to around 25,000, roughly the same range as the mouse (see Table 1–2). But the surprising thing is that these protein-encoding genes represent less than 2% of the 3.2 billion base pairs in the human genome.45 Unlike the even spacing of a string of pearls, our genes often cluster in gene-rich regions separated by gene-poor deserts.
Table 1–2. Genome sizes and gene density in humans as compared with other organisms frequently used in genetic research
|
Organism |
Estimated size (base pairs) |
Estimated gene number |
Average gene density |
Chromosome number |
|
Homo sapiens (human) |
3.2 billion |
~25,000 |
1 gene per 100,000 bases |
46 |
|
Mus musculus (mouse) |
2.6 billion |
~25,000 |
1 gene per 100,000 bases |
40 |
|
Drosophila melanogaster (fruit fly) |
137 million |
13,000 |
1 gene per 9,000 bases |
8 |
|
Arabidopsis thaliana (plant) |
100 million |
25,000 |
1 gene per 4,000 bases |
10 |
|
Caenorhabditis elegans (roundworm) |
97 million |
19,000 |
1 gene per 5,000 bases |
12 |
|
Saccharomyces cerevisiae (yeast) |
12.1 million |
6,000 |
1 gene per 2,000 bases |
32 |
|
Escherichia coli (bacteria) |
4.6 million |
3,200 |
1 gene per 1,400 bases |
1 |
|
H. influenzae (bacteria) |
1.8 million |
1,700 |
1 gene per 1,000 bases |
1 |
From Human Genome Project Information: Functional and Comparative Genomics Fact Sheet. www.ornl.gov/sci/techresources/Human_Genome/faq/compgen.shtml
The human genome is distributed between 23 chromosomes. These are found singly in sperm and eggs (haploid), but in pairs in all of the rest of our cells (diploid). This halving in chromosomes number in eggs and sperm is achieved during the two cell divisions of meiosis. During the first division, homologous paternal and maternal chromosomes pair respectively with paternal and maternal chromosomes assorting independently of each other. During the pairing, chromosome segments are exchanged between homologs, a process called genetic recombination (see Glossary for a brief introduction to Mendelian genetics). Although not generating new genetic alterations, the processes of independent assortment and recombination provide the opportunity to assort existing parental genes in a variety of new combinations. Creation of all of this new genetic variability on which natural selection can act is a major reason why sexual reproduction predominates in animals and plants.
Like the genes of other higher organisms, human genes themselves are not single blocks of DNA that encode specific proteins. Instead, they are broken up into coding sequences (exons) and noncoding sequences (introns). Following the process of transcription, when the information in a gene is copied into a messenger RNA molecule, the intron sequences are spliced out of the message so only the coding sequences in the messenger RNA can be translated into protein sequence.
What is all that other DNA doing that has no obvious genetic function? We know that at least 50% of the genome, perhaps more, is made up of repeated sequences that do not encode human proteins and often no proteins at all. These repeats are of several kinds, but the most abundant are "mobile" genetic elements that make up roughly 43% of the mammalian genome.46 They either are or at one time were capable of movement from one site in the genome to another.
Transposons are the first group of mobile elements. They comprise around 3% of the genome. The name transposon evokes the word transposition and, indeed, these elements are capable of moving from one to another place in the genome. The easiest way to think about transposition is as a "cut-and-paste" process. One cuts out a word, or a group of words, in a text and then pastes those words into a specific place elsewhere in the text. The important difference between transposition and cutting and pasting is that, although transposition will take place only into its target DNA sequence, the element can be pasted into that sequence anywhere in the genome. An enzyme called a transposase encoded by the element catalyzes the transposition process. Hence, transposons are sometimes called jumping genes.
The second group includes several sets of elements of which three are the most abundant. The first are endogenous retroviruses. These are viruses whose genetic material is RNA. An enzyme called a reverse transcriptase encoded by the virus catalyzes synthesis of DNA copies of the viral RNA. These DNA copies are then inserted into the genome. The AIDS virus is the best-known retrovirus, but unlike AIDS, the retroviral fragments that inhabit our genomes today are, for the most part, the remains of ancient retroviruses that have lost their ability to become independent of the genome.
LINES (long interspersed nuclear elements) comprise the second group (see Glossary for a more complete discussion of LINES and SINES). They are retrotransposons. One way to think about a retrotransposon is as an odd sort of printing press. An RNA copy is transcribed from the retrotransposon DNA. In the case of LINES, translation of the RNA copy results in the production of two proteins. One of these proteins is essential for the transposition process. The second catalyzes synthesis of a DNA copy of the RNA and then makes a cut in a specific DNA sequence (e.g., TTTTAA/AAAATT for L1) in the genome where the newly made retrotransposon can insert. This method of reproduction has the potential for enormously amplifying the number of retrotransposons in the genome that can then home into their target sequences wherever they are in the genome.
There are several different kinds of LINE elements, but L1, which predominates in the human genome, has evolved along with the mammals over the past 160 million years or more. Expansion in the number of L1s in the genome was rapid, but appears to have slowed down about 25 million years ago. The 500,000 or so copies of L1 present today in the human genome amount to around 18% of its content. The intact L1 element is about 6,000 base pairs in length, but truncated versions are common. L1s are the only active transposons in the human genome today.
SINES (short interspersed nuclear DNA elements) are short DNA sequences of less than 500 base pairs. SINES do not encode any proteins and are not autonomous. They can only transpose with the aid of the two proteins made by active LINE elements. The most important SINES are the Alu elements.47 More than a million copies of these short DNA sequences are found in the human genome. They represent around 13% of the total DNA. Alu elements originated and coordinated their amplification with the radiation of the primates about 65 million years ago.
Because nobody is exactly sure why human and other animal and plant genomes contain so many repeated elements, they have sometimes been treated as irritants with regard to the real genes, gaining them epithets such as "junk DNA" and "selfish DNA." In a recent review, Goodier and Kazazian point out that a more sophisticated name "dark matter" is coming into vogue for these repeated elements, acknowledging the fact that we don't really understand whether they have an as-yet-to-be-discovered function. Goodier and Kazazian prefer to think of mobile elements as "dark energy."48 They are "a dynamic force that not only accelerates expansion but also helps set the warp and weft of genomes for better and for worse. Transposable elements arose as intracellular parasites that became domesticated."
Well not entirely. Transposition of these elements can disrupt gene function. In a 1998 paper in Nature, Kazazian and his colleagues reported two unrelated cases of hemophilia A for which there was no family history, suggesting that the mutations had arisen de novo.49 Each of them involved the insertion of L1 sequences into the F8 gene. So we end this chapter where we began it—with hemophilia. Transposon insertions have also been implicated in a wide spectrum of genetic diseases other than hemophilia.50