26 March 2011

"Genetic dark matter" (SN: 12/18/10, p. 18) might be hiding in plain sight.  For over two decades, abundant variation in the number of tandemly repeated units in microsatellite and minisatellite DNA has been used for genetic fingerprinting.  For years, this variation has been widely regarded as functionally meaningless.  For much of that time, several biologists (including myself) have hypothesized that such repeat-number variation might help account for heritable variation in certain traits.

Most such repeats are indeed found in genomic regions that lack known function.  But among the hundreds of thousands of repeats scattered throughout the human genome are many that are closely associated with genes.  Lots of genes, perhaps most, include at least one variable tandem repeat sequence at sites where the number of repeat units can influence gene function.  Nevertheless, most attention (and most research investment) remains focused on single nucleotide polymorphisms (SNPs) for the very simple reason that collecting vast data sets on SNPs has become cheap and easy.  Although surveying repeat number variation and linking this variation with phenotypic differences are technically challenging, biologists should not lose sight of this very visible source of heritable variation.

Science News has covered some of the relevant studies in past articles (SN: 12/18/04, p. 387; SN: 1/31/09, p. 26).  The subject of repeat number variation might be suitable for an article that could shed light on many inter-related topics - triplet repeat diseases, evolutionary facilitation, molecular genetics, genomic diversity, etc.

David G. King, Carbondale, Ill.
King is an associate professor of zoology at Southern Illinois University.

Cited articles

SN: 12/18/10, p. 18
Saey, TH (2010) Genetic Dark Matter: Searching for new sources to explain human variation. Science News 178(13):18.

. . . [Biologists] are seeking an explanation for unknown sources of variation in heritable traits, the way physicists are searching for a mysterious substance dubbed dark matter that could explain puzzling aspects of the cosmos. . . . For most genome-wide association studies, . . . [researchers] identify a large number of genetic variants with small effects, but none add up to fully explain heritability.

Researchers know that the cause of the unexplained genetic variation, dubbed "missing heritability," must be out there somewhere. Like dark matter, says Olivier Harismendy, a genomicist at the University of California, San Diego, "we know it's there, but we just can't grasp it."

https://www.sciencenews.org/article/genetic-dark-matter

SN: 1/31/09, p. 26
Saey, TH (2009) Molecular Evolution: Investigating the genetic books of life reveals new details of 'descent with modification' and the forces driving it. Science News 175(3):26.

. . . [John Fondon's] team focused on repeats of amino acids within proteins. . . . Fondon reasoned that slightly altering the number of repeated amino acids, each of which are encoded by repeated three-letter DNA sequences, might subtly change the function of the protein, creating a variant that could be put to an evolutionary test. . . . "If what the protein does is a verb, a repeat is an adverb," says Fondon. The repeats don't change what the protein does; they just make it happen more quickly, slowly or frequently.

http://www.sciencenews.org/view/feature/id/40006/title/Molecular_Evolution

SN: 12/18/04, p. 387
Kibble for Thought: Dog diversity prompts new evolution theory. Science News 166(28):387.

  
Additional literature (theory and supporting evidence)

King, D.G., and Y. Kashi (2009)  Heretical DNA sequences?  Science 326: 229-230.  [html] [pdf]

Fondon III, J.W., E.A.D. Hammock, A.J. Hannan, and D.G. King (2008)  Simple sequence repeats: Genetic modulators of brain function and behavior.  Trends in Neurosciences 31: 328-334.  doi: 10.1016/j.tins.2008.03.006.   [authors' prepublication MSWord document]

King, D.G., and Y. Kashi (2007)  Mutation rate variation in eukaryotes: evolutionary implications of site-specific mechanisms.  Nature Reviews Genetics 8 (November 2007) | doi:10.1038/nrg2158-c1. 

King, D.G., and Y. Kashi (2007)  Mutability and Evolvability:  Indirect selection for mutability.  Heredity 99:123-124. doi:10.1038/sj.hdy.6800998. 

Y. Kashi and D.G. King (2006)  Simple Sequence Repeats as Advantageous Mutators in Evolution.  Trends in Genetics 22: 253-259.  [Abstract]  doi: 10.1016/j.tig.2006.03.005

King, D.G., M. Soller and Y. Kashi (1997)  Evolutionary tuning knobs.  Endeavour 21: 36-40.  [pdf]  [related page]

Y. Kashi, D.G. King, and M. Soller (1997)  Simple sequence repeats as a source of quantitative genetic variation.  Trends in Genetics 13: 74-78.  [Abstract]  [pdf]