Genetic detective

This isn't a post about CSI (although, I wouldn't mind working with Emily Procter ). This week the current issue of Nature is focused on personal genomics. Going along those lines is a pretty good Nature News story about the case of missing heritability .

Heritability refers to how much variance in a phenotype can be attributed to genetics. The Nature news story linked to above tries to explain why recent genomewide association studies have failed to uncover genes of large effect.

This year, three groups of researchers2,3,4 scoured the genomes of huge populations (the largest study4 looked at more than 30,000 people) for genetic variants associated with the height differences. More than 40 turned up.

But there was a problem: the variants had tiny effects. Altogether, they accounted for little more than 5% of height's heritability — just 6 centimetres by the calculations above. Even though these genome-wide association studies (GWAS) turned up dozens of variants, they did "very little of the prediction that you would do just by asking people how tall their parents are", says Joel Hirschhorn at the Broad Institute in Cambridge, Massachusetts, who led one of the studies3.

(Height is one of my favorite traits, maybe because I'm a tall drink of water).

Anyways, one of the reasons I really like human genetics is because I mind this problem of missing heritability fascinating. (And the main reason why I think at this point doing personal genome scans may not be as medically relevant as companies offering such services may lead you to think) I remember reading a review paper on genome wide association studies way back in 2005 (human genetics moves fast!) saying that until genome wide re-sequencing was much cheaper, typing SNPs throughout the genome was the next best thing. Well,in the same issue of Nature there are two papers about the sequencing of the first Asian and African genome. But a quote from David Goldstein in the news article cautions against forging ahead with massive sequencing without putting some more careful thought:

At some point it might make sense to stop using SNPs, and start sequencing whole genomes. Collins suggests that the NHGRI's 1,000 genomes project, which aims to sequence the genomes of at least 1,000 people from all over the world, could go a long way towards finding hidden heritability, and many more genomes may become possible as the price of sequencing falls.

Not everyone supports an all-out sequencing onslaught. Goldstein warns against continuing to "turn the crank" without devising a more rational approach, such as sequencing the genomes of people who exhibit extreme manifestations of diseases. "I'm not really sold on doing the sequencing version of what we did with [GWAS]," he says. "It's a big enough, costly enough job, that I think we want to think a little bit harder about exactly who gets re-sequenced."

In the past few years I've gotten interested in epigenetics and in particular finding out what proportion of phenotypic variance can be attributed to epigenetic effects. Granted, humans aren't the best organism to address the issue.

Epigenetics, changes in gene expression that are inherited but not caused by changes in genetic sequence, confuses things further. Feeding a mouse a certain diet, for example, can alter the coat colour not only in its children, but also in its children's children11. Here, the expression of a coat-colour gene is controlled by a type of DNA modification called methylation, but it's not completely clear how that methylation pattern is 'remembered' by the next generation. The idea that grandma's environment could affect future generations is controversial — and such effects would have been included in the heritability normally attributed to genes.

"This complicates everything," says Nadeau. "How do we sort out what great-grandfather and great-grandmother were exposed to when they were young and having children?" Model organisms might help. Nadeau has investigated testicular germ-cell tumours in mice that are analogous to a highly heritable cancer in humans. His group found that the effects of one weak, cancer-promoting gene, Dnd1Ter, are greatly enhanced by several other gene variants, and the boosted effects are passed on even if the genes that cause them are not12. "It's presumably transmitting its presence in some epigenetic way," says Nadeau. The mechanisms by which epigenetic inheritance might work are still disputed, though; marks such as methylation that direct gene expression during someone's life seem to be wiped clean in a new embryo. One possible explanation for Nadeau's observation, he says, is that RNA is being inherited alongside DNA through sperm or eggs.

While I agree with the Goldstein quote above, the fact that next-generation sequencing technologies are maturing and have made the cost of sequencing much cheaper, having this new tool will help geneticists find the missing heritability that's out there. And for me personally, while I'm about to embark on a PhD in next-generation sequencing informatics, deep down I really want to be a human geneticist because of mysteries like these.