Oct 13 2010
ost people can get their heads wrapped around the idea that genetic variation can occur by virtue of the presence (or lack) of a particular gene. And no doubt some of you understand the basis of the simple mutations that can influence gene function, such as point deletions (which would make you blood group O) or single nucleotide polymorphisms (SNPs) that might influence your susceptibility heart disease due to high homocysteine levels in your blood.
An additional method of variation is simply whether a person has more or less than the normal number of copies of a particular gene. Known as copy number variants (CNVs) these are segments of DNA in which differences in the number of copies of a particular gene (or other large sequence/region) have been found by comparison of two or more genomes. CNVs may vary for particular genetic regions due to a lower number (gene deletion) or a higher number (gene duplication).
CNVs have been shown to contribute to human evolution, genetic diversity between individuals, and a rapidly increasing number of traits or susceptibility to traits. CNVs can be limited to a single gene or include a contiguous set of genes. CNVs can result in having either too many or too few of the dosage sensitive genes, which may be responsible for a substantial amount of human phenotypic variability, complex behavioral traits, and disease susceptibility. (1) Evidence of CNVs have existed for decades – for example, the glutathione S-transferase, MU-1 gene (GSTM1) null genotype is found in about 50% in Europeans and their descendants.
CNVs are an important source of variation in the genome; at present only the tip of the “CNV iceberg” has been explored in relation to complex trait genetics. Like other types of genetic variation, some CNVs have been associated with susceptibility or resistance to disease. Unfortunately, our limited knowledge of the phenotypic effects of most CNVs has led to the classification of many CNVs as “genomic imbalances of unknown clinical significance.”
Pathogenic CNVs are associated not only with birth defects and cancers, but also with neurodevelopmental disorders at birth or neurodegenerative diseases in adulthood. (2) Gene copy number can be elevated in cancer cells. For instance, the epidermal growth factor receptor (EGFR) copy number can be higher than normal in non-small cell lung cancer.(3) A higher copy number of CCL3L1 has been associated with lower susceptibility to human HIV infection and a low copy number of FCGR3B (the CD16 cell surface immunoglobulin receptor) can increase susceptibility to systemic lupus erythematosus (SLE) and similar inflammatory autoimmune disorders.(4)
An interesting example of a CNV with real-world significance is the numeric differences between individuals for the gene AMY1 (salivary amylase), an enzyme found in saliva that breaks starch down into sugar. While there is a considerable range of variation in dietary starch intake among human populations, a distinction can be made between “high-starch” populations for which starchy food resources comprise a substantial portion of the diet, and the small fraction of “low-starch” populations with traditional diets that incorporate relatively few starchy foods. The presence of multiple copies of the amylase gene AMY1 was also shown to differ among populations based on their long-term access to carbohydrate diets. (5,6)
Salivary amylase gene (AMY1) copy number is correlated positively with salivary amylase protein levels, and that individuals from populations with high-starch diets have on average more AMY1 copies than those with traditionally low-starch diets. Higher AMY1 copy numbers and protein levels likely improve the digestion of starchy foods and may buffer against the fitness-reducing effects of intestinal disease. (7) The data indicate that members of an ancestral population such as Europeans or Africans share some copy number variants but each individual may have as much as 20% unique CNVs. (8)
Autism Spectrum Disorders
Autism spectrum disorders (ASDs) include a variety of conditions characterized by deficits in social interaction and verbal and nonverbal communication skills, as well as repetitious behaviors. Abnormal behaviors range from mild to severe, and cognitive abilities range from above average to intellectually disabled. Copy number variations have also been associated with autism (9-12) as well as schizophrenia (13) and idiopathic learning disability. (14)
Individuals diagnosed with (ASDs) have nearly 20% more gene copy number variations (CNVs) overall and more than 60% more CNVs in genes associated with intellectual disability or ASDs compared with matched control patients, according to a study published in the June 10 issue of Nature. (10)
Using blood samples from 996 elementary school-age children diagnosed on the autism spectrum from the United States, Canada, and Europe, the scientific teams combed the children’s DNA for rare deletions and duplications. In particular, they hunted for changes in the genetic information that a child inherits from each parent. The families consisted of parents with one autistic child.
The report by the Autism Genome Project Consortium — an international group of 120 scientists at more than 50 institutions who have shared their work on autism susceptibility genes since 2002 — implicated copy number variants in many new ASDs-linked genes, including SHANK2, SYNGAP1, and DLGAP2, whose gene products are located in postsynaptic densities.
SHANK3 encodes a “synaptic scaffolding protein” whose mutations were associated with ASDs in 2007. SYNGAP mutations have been reported in “autosomal nonsyndromic mental retardation,” and DLGAP family proteins interact with proteins in the postsynaptic density and are involved in neurotransmission.
Given that ASDs occur at least 4 times more frequently in boys than girls, it is also noteworthy that the study found 7 cases of maternally inherited deletions in the DDX53-PTCHD1 region of the X chromosome, all in boys with ASDs.
A functional map of ASDs included in the report by the Autism Genome Project Consortium shows considerable effects of CNVs on ASDs-linked genes controlling on glycosylation and cell-to-cell adhesion. This is not surprising, since many of these glycans participate in lectin-like attachments between neurons that characterize the neuroplasticity behind the neural networks involved in learning and memory.
A while back I wrote about some fascinating work being done to investigate the effects of the simple sugar (monosaccharide) fucose and its metabolism (fucosylation) on the modification of neuronal synapses –the connections between nerve cells that forge the networks that comprise, among other things, learning. In addition to being part of the antigenic structure of the H antigen found in blood group O, fucose is now garnering attention as an important component in learned behavior. It turns out that what goes into holding the synapse together may be as important a factor in cognition and learning as what jumps across the synapse. And that appears to be lectin-like receptors on one side of the nerve synapse which bind to fucose as a ligand on the other.
Reaction in the brain involving fucose skyrocket during periods of intense learning. Human milk is a very rich source of the sugar, with amounts far higher than all other species. The sugar content of human milk varies by the same fucosyltransferase enzymes FUT1, FUT2 and FUT3 that code for ABO and Lewis blood groups and and ABH secretor status (15-17). Interestingly, fucosyltransferases (or at least the fucosyltransferases that control secretor phenotype) appear to be linked serum B12 levels. (18)
Fucose and fucosylation have a big role in ontogeny (the origin and the development of an organism from the fertilized egg to its mature form) via it’s role in the development of the Lewis X antigen (FUT9) which supports cell-to-cell-adhesion in embryos. Lewis X expression in the brain is in turn controlled by the PAX6 gene, which regulates many elements of nerve growth in addition to forming the architecture of the iris.
Turns out that fucose is not that easy to find in Nature or the diet. There is a bit of it in Brewer’s yeast and certain mushrooms, but by far the greatest concentration is found in seaweeds, in particular the brown seaweeds such as bladderwrack (Fucus vesiculosis) and kelps of the genus Laminaria.
Fucus contains a wide spectrum of interesting polysaccharides (complex chains of sugars) known as fucoidans and fucans. In general, fucoidans are a family of high molecular weight sulfated polysaccharides, widely dispersed in the cell walls of brown seaweed. The core region (or backbone) of fucoidan is composed primarily of a repeating chain of fucose sugars. Fucose is also attached to this backbone, forming branch points at every 2-3 fucose residues within the chain.
The fucoidan found in bladderwrack has been reported to reduce inflammatory brain damage and rats given fucoidan treatment after collagenase-induced intracerebral hemorrhage had reduced inflammation in the vicinity of the hematoma after three days while also showing significantly more rapid improvement of motor function in the first week following hemorrhage and better memory retention. (19)
Could sprinkling a little kelp on a salad help boost fucosylation, improve memory or enhance nerve synapse adhesion? Who knows! But ruling out sensitivities to iodine and a need to restrict sodium (other nutrients that tend to be found in kelps) it might be a worthwhile experiment to try for a while. Human breast milk is the most fucosylated of all mammals (153 human milk oligosaccharides to a paltry 23 in our bovine breathren) so perhaps John D. Rockefeller, who reportedly hired a wet nurse in his old age to give him breast milk, was on to something after all. Turns out the old boob-snuggler lived to be 98.
- Cook EH, Scherer SW. Copy-number variations associated with neuropsychiatric conditions. Nature 455 (7215): 919–23. (2008)
- Cappuzzo F, Hirsch, et al. (2005). Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. Journal of the National Cancer Institute 97 (9): 643–655
- Choy KW, Setlur SR, Lee C, Lau TK.The impact of human copy number variation on a new era of genetic testing.BJOG. 2010 Mar;117(4):391-8. Epub 2010 Jan 26.
- Aitman T. J. et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439 (7078): 851–855. (2006)
- Perry GH, Dominy NJ, Claw KG, Lee AS, Fiegler H, Redon R, Werner J, Villanea FA, Mountain JL, Misra R, Carter NP, Lee C, and Stone AC. Diet and the evolution of human amylase gene copy number variation. Nat Genet (2007) 39(10): p. 1256-60
- Novembre J, Pritchard JK, and Coop G. Adaptive drool in the gene pool. Nat Genet (2007) 39(10): p. 1188-90
- Orozco LD, Cokus SJ, Ghazalpour A, Ingram-Drake L, Wang S, van Nas A, Che N, Araujo JA, Pellegrini M, and Lusis AJ. Copy number variation influences gene expression and metabolic traits in mice. Hum Mol Genet (2009)
- McElroy JP, Nelson MR, Caillier SJ, and Oksenberg JR. Copy number variation in African Americans. BMC Genet (2009) 10 : p. 15
- Shaikh TH, Gai X, Perin JC, Glessner JT, Xie H, Murphy K, O’Hara R, Casalunovo T, Conlin LK, D’Arcy M, Franckelton EC, Geiger EA, Haldeman-Englert C, Imielinski M, Kim CE, Medne L, Annaiah K, Bradfield J, Dabaghyan E, Eckert A, Onyiah CC, Ostapenko S, Otieno FG, Santa E, Shaner JL, Skraban R, Smith RM, Elia J, Goldmuntz E, Spinner NB, Zackai EH, Chiavacci RM, Grundmeier R, Rappaport EF, Grant SF, White PS, and Hakonarson H. High-resolution mapping and analysis of copy number variations in the human genome: A data resource for clinical and research applications. Genome Res (2009)
- Pinto D, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010 Jun 9.
- Sebat, J., et al. Strong association of de novo copy number mutations with autism. Science 316 (5823): 445 (2007)
- Cook EH, Scherer SW. Copy-number variations associated with neuropsychiatric conditions. Nature 455 (7215): 919–23. (2008)
- Nöthen MM, Nieratschker V, Cichon S, Rietschel M. New findings in the genetics of major psychoses. Dialogues Clin Neurosci. 2010;12(1):85-93.
- Knight, S., et al. Subtle chromosomal rearrangements in children with unexplained mental retardation. The Lancet 354: 1676. (1999)
- Erney R, Hilty M, Pickering L, Ruiz-Palacios G, Prieto P.Human milk oligosaccharides: a novel method provides insight into human genetics.Adv Exp Med Biol. 2001;501:285-97
- D’Adamo PJ, Kelly GS.Metabolic and immunologic consequences of ABH secretor and Lewis subtype status. Altern Med Rev. 2001 Aug;6(4):390-405
- Kobata A.Structures and application of oligosaccharides in human milk. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(7):731-4
- Hazra A, Kraft P, Selhub J, Giovannucci EL, Thomas G, Hoover RN, Chanock SJ, Hunter DJ.Common variants of FUT2 are associated with plasma vitamin B12 levels.Nat Genet. 2008 Oct;40(10):1160-2. Epub 2008 Sep 7. Link
- Del Bigio MR, Yan HJ, Campbell TM, Peeling J.Effect of fucoidan treatment on collagenase-induced intracerebral hemorrhage in rats.Neurol Res. 1999 Jun;21(4):415-9.Link