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Our Missing Genes

New research suggests that the average person has about 20 genes with loss-of-function mutations—many more than previously suspected.

By | February 17, 2012

image: Our Missing Genes Flickr, MJ/TR (´???)

FLICKR, MJ/TR

New research published today (February 17) in Science suggests that our genomes, even those from healthy people, may harbor a surprising number of missing and mutated genes, reports ScienceNOW. Using 185 individual genome sequences from the 1000 Genomes Project, an international team of researchers identified 2,951 mutations that, rather than being sequencing errors, might instead be “loss-of-function” mutations that cripple their genes.

The researchers culled 1,285 mutations from this pool using stringent filtering to identify the mutations most likely to result in loss of function. Of these, 100 are found frequently in European genomes. On average, a person will have about 20 genes that are completely “lost”—meaning that both alleles have inactivating mutations. Given the apparent high rate of such mutations, the researchers write that there is “need for caution in assigning disease-causing status to novel gene-disrupting variants found in patients.”

"This shows how careful we need to be when drawing inferences about such mutations," geneticist Peter Visscher of the University of Queensland in Australia, who was not involved in the research, told ScienceNOW.

 

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Avatar of: HFletcher_679

HFletcher_679

Posts: 44

February 18, 2012

This result should not be surprising. One of the most interesting discoveries to come from genome sequencing from yeast onwards was that about 1/3rd of genes don't seem to be necessary. Removing them individually does not cause any observable phenotypic effect. They are either partially redundant because another similar gene product hides their individual loss, or because the value by which they increase fitness is too small to notice. Because there is little selection for them they will exist as nul mutations at a fairly high frequency. At equilibrium, loss by selection equals production of new mutations, known as mutational load. A typical loss-of-function mutation rate per gene is about 1 in 100,000. If total (homozygous) loss of a gene product reduces fitness by 0.001 (1 thousandth) then at equilibrium roughly 10% of all alleles of that gene will be inactivated mutants, giving 1,000 homoxygous mutants in a population of 100,000, one of which will be sacrificed to selection to remove two mutant alleles, balancing against new mutations. That level of selection is ample to maintain the gene in a large population. Isn't population genetics wonderful?
I like to use the example of wheelnuts on cars to teach this. Most car wheels are held on by 4 or 5 nuts. If one of these is lost then the average family car will still function normally, but for a very small number of drivers tuning corners at high speed on a very bumpy road the strain on the wheel fixing may be too great, and the wheel will loosen with disasterous effects. More likely, a few cars will lose a second nut, and the combined effect will produce a malfunction. For wheel nut, substitute gene with high frequency of inactivating alleles, as described here.

Avatar of:

Posts: 0

February 18, 2012

This result should not be surprising. One of the most interesting discoveries to come from genome sequencing from yeast onwards was that about 1/3rd of genes don't seem to be necessary. Removing them individually does not cause any observable phenotypic effect. They are either partially redundant because another similar gene product hides their individual loss, or because the value by which they increase fitness is too small to notice. Because there is little selection for them they will exist as nul mutations at a fairly high frequency. At equilibrium, loss by selection equals production of new mutations, known as mutational load. A typical loss-of-function mutation rate per gene is about 1 in 100,000. If total (homozygous) loss of a gene product reduces fitness by 0.001 (1 thousandth) then at equilibrium roughly 10% of all alleles of that gene will be inactivated mutants, giving 1,000 homoxygous mutants in a population of 100,000, one of which will be sacrificed to selection to remove two mutant alleles, balancing against new mutations. That level of selection is ample to maintain the gene in a large population. Isn't population genetics wonderful?
I like to use the example of wheelnuts on cars to teach this. Most car wheels are held on by 4 or 5 nuts. If one of these is lost then the average family car will still function normally, but for a very small number of drivers tuning corners at high speed on a very bumpy road the strain on the wheel fixing may be too great, and the wheel will loosen with disasterous effects. More likely, a few cars will lose a second nut, and the combined effect will produce a malfunction. For wheel nut, substitute gene with high frequency of inactivating alleles, as described here.

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