Monday, April 28, 2008

The genetic basis of height

Nature Genetics has a commentary piece and three research papers looking at genetic variants associated with variation in height. First of all, from the commentary piece, we learn that height has a heritability of 0.8, so 80% of variation in height is due to variation in genetics.
The three studies look at hundreds of thousands of SNPs among a total of 63,000 people. Surprisingly they find little overlap in terms of variants that are associated with height in all three studies (variants in only three genes across all three studies, and 7 genes in 2 out of three studies), perhaps due to statistical issues having to do with testing so many variants at once. They find a total of 54 variants that are associated with variation in height, all of them with small effects.
They find no differences between males and females, and no evidence of interaction between alleles.
Throughout this article, the author breaks down the costs and benefits of the various approaches of getting at genotype-phenotype relationships, and discusses some of the other major hurdles in the process.

Thursday, April 24, 2008

MAOA variant and delinquent behavior

I thought I would post this abstract because I find a lot of my students are interested in the genetic basis for criminal/violent behavior. One of the hws I usually give them is to imagine they had 1 million dollars to gather genetic data in regard to some human trait-- how/what would they do? - and violent/criminal behavior is one of the more popular responses along with addiction, disease etc...
In this paper, they are nicely explicit about their questions and hypotheses:
The objective of this study is twofold. The First, to investigate the association between the self-reported serious and violent delinquency and the 30-bp VNTR in the MAOA gene in a cohort of 2524 adolescents and young adults in the United States in the National Longitudinal Study of Adolescent Health (Add Health). The specific hypothesis is that the MAOA 2R is associated with higher levels of delinquency. Second, to perform a functional analysis that evaluates the promoter activity in an MAOA 1.3-kb promoter-luciferase construct containing 2-, 3-, and 4-repeat sequences of the 30-bp VNTR, using two human brain-derived cell lines: neuroblastoma SH-SY5Y and human glioblastoma 1242-MG.
...and basic conclusion:
The present study demonstrated a link between the 2 repeat of the 30-bp VNTR in the MAOA gene and much higher levels of self-reported serious and violent delinquency...
The VNTR 2 repeat in MAOA and delinquent behavior in adolescence and young adulthood: associations and MAOA promoter activity
Guang Guo, Xiao-Ming Ou, Michael Roettger and Jean C Shih
European Journal of Human Genetics (2008) 16, 626–634

Abstract: Genetic studies of delinquent and criminal behavior are rare in spite of the wide recognition that individuals may differ in their propensity for delinquency and criminality. Using 2524 participants in Add Health in the United States, the present study demonstrates a link between the rare 2 repeat of the 30-bp VNTR in the MAOA gene and much higher levels of self-reported serious and violent delinquency. The evidence is based on a statistical association analysis and a functional analysis of MAOA promoter activity using two human brain-derived cell lines: neuroblastoma SH-SY5Y and human glioblastoma 1242-MG. The association analysis shows that men with a 2R report a level of serious delinquency and violent delinquency in adolescence and young adulthood that were about twice (CI: (0.21, 3.24), P=0.025; and CI: (0.37, 2.5), P=0.008 for serious and violent delinquency, respectively) as high as those for participants with the other variants. The results for women are similar, but weaker. In the functional analysis, the 2 repeat exhibits much lower levels of promoter activity than the 3 or 4 repeat.

Wednesday, April 23, 2008

Maternal diet influences sex of offspring

Here's some more support for the Trivers-Willard hypothesis that states that it's better to have males when resource conditions are good, since male reproductive success is less constrained than female reproductive success (although not as "guaranteed", especially in bad resource conditions).
Here they find that maternal diet at conception is associated with sex of offspring. They find some weird results having to do with breakfast cereal and discuss this in quite some length.

You are what your mother eats: evidence for maternal preconception diet influencing foetal sex in humans
Fiona Mathews, Paul J. Johnson, Andrew Neil
Proceedings of the Royal Society B Online April 22,2008

Abstract: Facultative adjustment of sex ratios by mothers occurs in some animals, and has been linked to resource availability. In mammals, the search for consistent patterns is complicated by variations in mating systems, social hierarchies and litter sizes. Humans have low fecundity, high maternal investment and a potentially high differential between the numbers of offspring produced by sons and daughters: these conditions should favour the evolution of facultative sex ratio variation. Yet little is known of natural mechanisms of sex allocation in humans. Here, using data from 740 British women who were unaware of their foetus's gender, we show that foetal sex is associated with maternal diet at conception. Fifty six per cent of women in the highest third of preconceptional energy intake bore boys, compared with 45% in the lowest third. Intakes during pregnancy were not associated with sex, suggesting that the foetus does not manipulate maternal diet. Our results support hypotheses predicting investment in costly male offspring when resources are plentiful. Dietary changes may therefore explain the falling proportion of male births in industrialized countries. The results are relevant to the current debate about the artificial selection of offspring sex in fertility treatment and commercial ‘gender clinics’.

Do clines of genetic diversity say anything about migration patterns?

P-ter at GNXP discusses this Nature Genetics paper. The important point is that the maps of gradients of genetic similarity made famous by Cavalli-Sforza do not necessarily tell us anything about the pattern, direction, or speed of migrations of humans across continents.

Interpreting principal component analyses of spatial population genetic variation
John Novembre & Matthew Stephens
Nature Genetics Published online: 20 April 2008

Nearly 30 years ago, Cavalli-Sforza et al. pioneered the use of principal component analysis (PCA) in population genetics and used PCA to produce maps summarizing human genetic variation across continental regions1. They interpreted gradient and wave patterns in these maps as signatures of specific migration events1, 2, 3. These interpretations have been controversial4, 5, 6, 7, but influential8, and the use of PCA has become widespread in analysis of population genetics data9, 10, 11, 12, 13. However, the behavior of PCA for genetic data showing continuous spatial variation, such as might exist within human continental groups, has been less well characterized. Here, we find that gradients and waves observed in Cavalli-Sforza et al.'s maps resemble sinusoidal mathematical artifacts that arise generally when PCA is applied to spatial data, implying that the patterns do not necessarily reflect specific migration events. Our findings aid interpretation of PCA results and suggest how PCA can help correct for continuous population structure in association studies.

Thursday, April 17, 2008

The developmental overnutrition hypothesis tested

What is this hypothesis?
Children become obese because their mothers were obese during pregnancy and this disrupts the offspring's appetite control and energy metabolism.
I wonder what the evolutionary basis for this hypothesis would be?

They use the FTO genotype and mendelian randomization to test it, and find little support for it.

Exploring the Developmental Overnutrition Hypothesis Using Parental–Offspring Associations and FTO as an Instrumental Variable

Debbie A. Lawlor, Nicholas J. Timpson, Roger M. Harbord, Sam Leary, Andy Ness, Mark I. McCarthy, Timothy M. Frayling, Andrew T. Hattersley, George Davey Smith
PLoS Medicine

Background The developmental overnutrition hypothesis suggests that greater maternal obesity during pregnancy results in increased offspring adiposity in later life. If true, this would result in the obesity epidemic progressing across generations irrespective of environmental or genetic changes. It is therefore important to robustly test this hypothesis.

Methods and Findings We explored this hypothesis by comparing the associations of maternal and paternal pre-pregnancy body mass index (BMI) with offspring dual energy X-ray absorptiometry (DXA)–determined fat mass measured at 9 to 11 y (4,091 parent–offspring trios) and by using maternal FTO genotype, controlling for offspring FTO genotype, as an instrument for maternal adiposity. Both maternal and paternal BMI were positively associated with offspring fat mass, but the maternal association effect size was larger than that in the paternal association in all models: mean difference in offspring sex- and age-standardised fat mass z-score per 1 standard deviation BMI 0.24 (95% confidence interval [CI]: 0.22 to 0.26) for maternal BMI versus 0.13 (95% CI: 0.11, 0.15) for paternal BMI; p-value for difference in effect less than 0.001. The stronger maternal association was robust to sensitivity analyses assuming levels of non-paternity up to 20%. When maternal FTO, controlling for offspring FTO, was used as an instrument for the effect of maternal adiposity, the mean difference in offspring fat mass z-score per 1 standard deviation maternal BMI was −0.08 (95% CI: −0.56 to 0.41), with no strong statistical evidence that this differed from the observational ordinary least squares analyses (p = 0.17).

Conclusions Neither our parental comparisons nor the use of FTO genotype as an instrumental variable, suggest that greater maternal BMI during offspring development has a marked effect on offspring fat mass at age 9–11 y. Developmental overnutrition related to greater maternal BMI is unlikely to have driven the recent obesity epidemic.

Monday, April 14, 2008

Svante Paabo interview in PLoS Genetics

Svante Paabo is best known for his work with ancient DNA, including Neanderthals.

Two of the more interesting parts of the interview:

1) How to determine if there's DNA in an ancient sample:

What you actually do is a several stage process, where you first take very small samples, of say 10 mg, and just see if there are amino acids preserved—the amino acid profile of collagen. If there is no collagen preservation, it turns out there is hardly ever DNA. We can already exclude a lot of remains that way. And then we take samples of 100–200 mg, extract DNA, and see if we can find Neanderthal DNA. And then for the genome project where we need larger samples, we use bones that have very little morphological information.

So in the Museum in Zagreb, which houses the Vindija remains, we screen bones of which it cannot be said from the morphology if they are human or animal. By doing extraction from 100 mg, you can determine the species from the mitochondrial DNA. So the paleontologists gain something—they learn what species the different bones come from, and so it is easy to justify taking half a gram from them if they turn out to be Neanderthal bones.
2) and, given his interest in Egypt, he talks about this idea of looking at geography and genes along the Nile, which sounds very interesting:
But coming back to Egypt again, what I would really like to do is have a boat and sail along the Nile from the Mediterranean, where people are really “European-like” to the source of the Nile in Lake Victoria, where people are really “African-like”, and sample every 50 kilometers along this corridor through the Sahara and just see how this transition occurs. Are there sharp borders or is there a gradient? And that would be a powerful thing to look at, and it would be feasible.

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