BUSY!!!

I haven't posted anything in a while and won't post anything for another couple of weeks, but I'll be back with a vengeance in mid-April.

Quadrupedal humans - apparently not a hoax

I heard about these people in Turkey with a "throwback phenotype" a while ago, but was pretty skeptical. Now there's a paper in PNAS (see abstract below) about the possible genetic basis for it.
They suggest that altered brain activity patterns are what contribute to this phenotype: something that I wouldn't have guessed at first. I would have thought that there was something about their skeletal or muscular morphology that contributes to the ability or desire to do this (like, it just feels more comfortable to walk that way). But apparently these people have cerebellar hypoplasia.
If you look at the paper, there are some references to videos of these people.
Surprisingly the genetic basis for this trait is heterogeneous. Not all of them have the same genetic association.
from the conclusion:

In conclusion, we suggest that VLDLR-deficiency in the brain at a key stage of development leads to abnormal formation of the neural structures that are critical for gait. Given the heterogeneity of causes of quadrupedal gait, identification of the genes in families B and C promises to offer insights into neurodevelopmental mechanisms mediating gait in humans.

Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans
Tayfun Ozcelik, Nurten Akarsu, Elif Uz, Safak Caglayan, Suleyman Gulsuner, Onur Emre Onat, Meliha Tan, and Uner Tan
PNAS Published online on March 7, 2008

Abstract Quadrupedal gait in humans, also known as Unertan syndrome, is a rare phenotype associated with dysarthric speech, mental retardation, and varying degrees of cerebrocerebellar hypoplasia. Four large consanguineous kindreds from Turkey manifest this phenotype. In two families (A and D), shared homozygosity among affected relatives mapped the trait to a 1.3-Mb region of chromosome 9p24. This genomic region includes the VLDLR gene, which encodes the very low-density lipoprotein receptor, a component of the reelin signaling pathway involved in neuroblast migration in the cerebral cortex and cerebellum. Sequence analysis of VLDLR revealed nonsense mutation R257X in family A and single-nucleotide deletion c2339delT in family D. Both these mutations are predicted to lead to truncated proteins lacking transmembrane and signaling domains. In two other families (B and C), the phenotype is not linked to chromosome 9p. Our data indicate that mutations in VLDLR impair cerebrocerebellar function, conferring in these families a dramatic influence on gait, and that hereditary disorders associated with quadrupedal gait in humans are genetically heterogeneous.

Identical twins differ at DNA sequence level

An article in the NYT reports on the findings that were recently published in AJHG (see abstract below), where they find differences at the sequence level between identical twins (at least for CNVs).
I've seen interesting blog posts on this topic at Eye on DNA where there is a discussion of how we might be able to establish paternity if one of two identical twins could be the father and John Hawks who discusses the implications for heritability and disease studies.
I'm taking a quick look at the paper now, wondering if anyone has ever found SNP differences between identical twins, don't see anything about that, but it looks like they don't find any differences in their study:

The ten NTR MZ twins were genotyped on the SNP beadchip containing more than 300,000 SNPs, and genotypes were concordant for all SNPs.

and this is interesting, regarding the relative amount of variation due to CNVs compared to SNPs:

In one comprehensive recentstudy,14 it has been suggested that the total amount of sequence variation involving CNVs between two normal subjects is actually higher than that for single-nucleotide polymorphisms(SNPs).

Phenotypically Concordant and Discordant Monozygotic Twins Display Different DNA Copy-Number-Variation Profiles
Carl E.G. Bruder, et al.
The American Journal of Human Genetics, Volume 82, Issue 3, 763-771, 3 March 2008

Abstract: The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups. These findings have an impact on our views of genotypic and phenotypic diversity in monozygotic twins and suggest that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci. Our results also imply that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics.

Still more on climate and metabolic "disease" genes

Dan MacArthur at Genetic Future has looked more closely at the recent climate-metabolic genes paper that I briefly touched on (here, here). He makes the point that the correlation between allele frequency and temperature (for example) need not be linear and will differ by population depending on its' particular history:

... Native Americans, for instance, are the descendants of a cold-adapted population living in Siberia that only relatively recently moved down into the warmer climates of central America; selection has not yet had much time to act in these populations. In contrast, humans in Southern Asia have been in their current climate much longer, giving selection more time to do its work. Thus for variants under positive selection, current frequency will be substantially affected by historical contingencies, and the correlation between allele frequency and selective strength will be rough at best.

Dan also finds that only one of the sixteen genes that they examine shows any signs of positive selection using the iHS measure of selection.
His main argument is that balancing selection would probably better explain the pattern they find than positive selection. I think the main thrust behind his argument is the last paragraph:

A heterozygote advantage situation should be seen as an imperfect and temporary solution to the problem of adaptation, one that evolution uses during the earliest phase of adaptation in the absence of anything better. Ultimately, human populations are likely to stumble across more elegant long-term solutions: fixation (by positive selection) of more subtle "tweaking" mutations that adapt the population to its local climate, without the troublesome handicap of also causing disease in homozygotes. Once this has happened, studies such as this one based on simple allele frequency would be completely unable to uncover climate adaptation genes.

Razib has commented on this post also and is somewhat skeptical about the importance of balancing selection. At some point I will really read this paper more closely. I even printed it out a few days ago!

Genomics companies, health risks, and personalized health interventions... can they really say much?

..basically, we're still years away from being able to tell people about their health risks or about how they should eat/behave based on their genetic information. The authors of this paper (in AJHG, see abstract below) look in published meta analyses to assess the strength of the evidence for associations between the polymorphisms that companies test and disease risk. I wish they would have discussed some of the more promising gene-disease associations, and talked about what we can learn from those cases.

the companies they looked at (I've never heard of any of them):

... identified seven companies that offer predictive genetic testing using multiple markers (Genelex, Genovations,Genosolutions, Integrative Genomics, Salugen, Scionaand Suracell).

what these companies test:

The seven companies tested at least 69 different polymorphismsin 56 genes (Table S1). Only one gene (MTHFR [MIM 07093]) was tested by all seven companies, seven genes (CETP [MIM 118470], COL1A1 [MIM 120150], GSTM1 [MIM 138350], GSTP1 [MIM 134660], IL-6 [MIM
147620], TNF-a [MIM 191160], and VDR [MIM 601769])were tested by five or six companies, and 19 genes (34%) were tested by only one company.

what the published meta analyses of the genes shows:

Of the 160 unique polymorphism-disease associations that had been examined by meta-analysis, 60 were statistically significant (Figure 1 and Table S2), including significant associations for 29 of 69 polymorphisms in 25 (45%) of the 56 genes. However, statistically significant associations were generally modest, with significant odds ratios (ORs) ranging from 0.54 to 0.88 for protective allelesor genotypes and from 1.04 to 1.50 for risk alleles or genotypes,...

and:

On average, meta-analyses showed a significant association with disease risk for 58% of the genes included in each profile (range 38%–83%) (Table 1). These significant associations, however, were often with risk for disease outcomes other than those associated with the ‘‘profile’’

BUT:

The review did not assess the scientific basis of gene-expression profiles and pharmacogenomic applications. Although there may be applications that have stronger scientific support than others, there are clearly promising developments in this area.13,14

and,

Because the genetic profiles of the companies are offered to the general public, we restricted our search to meta-analyses of studies that included healthy or general-population controls. Because the predictive value of genetic testing depends on disease risk, genotype frequencies, and odds ratios for the association between disease risk and polymorphisms in a particular genetic profile, all of which may differ betweenpopulations, the profiles should be evaluated in the target population.15

about how single genes, like my favorite, MTHFR, can be associated with risk AND protective effects:

Furthermore, several genes, such as ACE [MIM 106180], APOE, and MTHFR, increase people’s risk for some diseases and decrease their risk for others (Table S2). For example, MTHFR 677TT was associated with an increased risk for depression, stroke, coronary artery disease, gastric cancer, schizophrenia, and venous thrombosis, but it was associated with a decreased risk for colorectal cancer. Hence, the putative health effects of preventive interventions tailored to a person’s MTHFR genotype may not be entirely beneficial.

A Critical Appraisal of the Scientific Basis of Commercial Genomic Profiles Used to Assess Health Risks and Personalize Health Interventions
A. Cecile J.W. Janssens, Marta Gwinn, Linda A. Bradley, Ben A. Oostra, Cornelia M. van Duijn and Muin J. Khoury
American Journal of Human Genetics, Volume 82, Issue 3, 593-599, 3 March 2008

Abstract: Predictive genomic profiling used to produce personalized nutrition and other lifestyle health recommendations is currently offered directly to consumers. By examining previous meta-analyses and HuGE reviews, we assessed the scientific evidence supporting the purported gene-disease associations for genes included in genomic profiles offered online. We identified seven companies that offer predictive genomic profiling. We searched PubMed for meta-analyses and HuGE reviews of studies of gene-disease associations published from 2000 through June 2007 in which the genotypes of people with a disease were compared with those of a healthy or general-population control group. The seven companies tested at least 69 different polymorphisms in 56 genes. Of the 56 genes tested, 24 (43%) were not reviewed in meta-analyses. For the remaining 32 genes, we found 260 meta-analyses that examined 160 unique polymorphism-disease associations, of which only 60 (38%) were found to be statistically significant. Even the 60 significant associations, which involved 29 different polymorphisms and 28 different diseases, were generally modest, with synthetic odds ratios ranging from 0.54 to 0.88 for protective variants and from 1.04 to 3.2 for risk variants. Furthermore, genes in cardiogenomic profiles were more frequently associated with noncardiovascular diseases than with cardiovascular diseases, and though two of the five genes of the osteogenomic profiles did show significant associations with disease, the associations were not with bone diseases. There is insufficient scientific evidence to conclude that genomic profiles are useful in measuring genetic risk for common diseases or in developing personalized diet and lifestyle recommendations for disease prevention.

Selection signatures at melanogenic genes TYR, TYRP1, and DCT

First, they find no difference in expression profiles between dark and light skinned melanocytes and between irradiated vs. unirradiated melanocytes. They attribute this to the presence of a growth factor in the media, but also say:

In any case, the homogeneity found in the gene expression profiles of human
melanocytes grown in BSE-containing media suggests that melanocytes from both
light and dark pigmentation donors may have the same genetic ability to produce
melanin if subject to the same level of external (paracrine) signaling molecules, at least above a certain concentration.

I haven't heard of this before!:

Alternative mechanisms to explain a possible adaptive advantage of dark pigmentation involve concealment [39]...
39. Robins AH: Biological perspectives on human pigmentation.
Cambridge Studies in Biological Anthropology. Cambridge, UK: Cambridge
University Press; 1991.

and

However, in the light of the apparent vagaries that occur in the pigmentation of mammalian skin, including primates, others [41] suggest that dark skin may have outlived its usefulness.
41. Montagna W, Prota G, Kenney JA: Black skin: structure and function.
New York: Academic Press; 1993.

They also sequence TYR, TYRP1 and DCT among Africans, Europeans, Asians, and Australian Aboriginies

In addition, it seems likely that nondirectional selection is acting too. For instance, overdominance seems compatible with the diversity patterns observed for DCT in Europeans. Similarly, the high frequency of the ancestral TYR haplotype within the Senegalese suggests that purifying selection at this locus may have been of some importance within Africa, although the large number of TYR mutations associated with oculocutaneous albinism 1 (OCA1) (OMIM#230100) suggest that TYR may be a gene under purifying selection in all populations.

in conclusion:

As a result, the lighter skin pigmentation phenotype in Europeans and East Asians may have been acquired by alternative mechanisms and thus, as previously suggested [11, 12, 13, 15], light skin would be the result of convergent evolution. Similarly, the diversity profile of Australian Aborigines suggests that this may also be the case for dark skin.

I think it's kind of weird how this paper seems like two separate studies put together, one on expression profiles of melanocytes and one on sequencing the three genes in different populations.

Complex signatures of selection for the melanogenic loci TYR, TYRP1 and DCT in humans
Santos Alonso, Neskuts Izagirre, Isabel Smith-Zubiaga, Jesus Gardeazabal, Jose Luis Diaz-Ramon, Jose Luis Diaz-Perez, Diana Zelenika, Maria Dolores Boyano, Nico Smit and Concepcion de la Rua
BMC Evolutionary Biology 2008, 8:74doi:10.1186/1471-2148-8-74

Abstract (provisional) Background The observed correlation between ultraviolet light incidence and skin color, together with the geographical apportionment of skin reflectance among human populations, suggests an adaptive value for the pigmentation of the human skin. We have used Affymetrix U133a v2.0 gene expression microarrays to investigate the expression profiles of a total of 9 melanocyte cell lines (5 from lightly pigmented donors and 4 from darkly pigmented donors) plus their respective unirradiated controls. In order to reveal signatures of selection in loci with a bearing on skin pigmentation in humans, we have resequenced between 4 to 5 kb of the proximal regulatory regions of three of the most differently expressed genes, in the expectation that variation at regulatory regions might account for intraespecific morphological diversity, as suggested elsewhere. Results Contrary to our expectations, expression profiles did not cluster the cells into unirradiated versus irradiated melanocytes, or into lightly pigmented versus darkly pigmented melanocytes. Instead, expression profiles correlated with the presence of Bovine Pituitary Extract (known to contain a-MSH) in the media. This allowed us to differentiate between melanocytes that are synthesizing melanin and those that are not. TYR, TYRP1 and DCT were among the five most differently expressed genes between these two groups. Population genetic analyses of sequence haplotypes of the proximal regulatory flanking-regions included Tajima's D, HEW and DHEW neutrality tests analysis. These were complemented with EHH tests (among others) in which the significance was obtained by a novel approach using extensive simulations under the coalescent model with recombination. We observe strong evidence for positive selection for TYRP1 alleles in Africans and for DCT and TYRP1 in Asians. However, the overall picture reflects a complex pattern of selection, which might include overdominance for DCT in Europeans. Conclusions Diversity patterns clearly evidence adaptive selection in pigmentation genes in Africans and Asians. In Europeans, the evidence is more complex, and both directional and balancing selection may be involved in light skin. As a result, different non-African populations may have acquired light skin by alternative ways, and so light skin, and perhaps dark skin too, may be the result of convergent evolution.

Full genome sequencing as a luxury good

Another article in the New York Times (via the Genetic Genealogist), this time about: What kind of people are shelling out the big bucks to get their genome sequenced?
This one guy featured in the article became the second person to get his entire genome sequenced, costing him $350,000, which I guess isn't too much if you're a multi-millionaire. The company Knome (pronounced: know me) did it.
This is pretty cool:

He says he will check discoveries about genetic disease risk against his genome sequence daily, “like a stock portfolio.”

this is kinda ridiculous:

Biologists have mixed feelings about the emergence of the genome as a luxury item. Some worry that what they have dubbed “genomic elitism” could sour the public on genetic research that has long promised better, individualized health care for all.

I wonder who this mystery Middle East man could be?:

But for now, Knome’s prospective customers are decidedly high-end. The company has been approached by hedge fund managers, Hollywood executives and an individual from the Middle East who could be contacted only through a third party, said Jorge Conde, Knome’s chief executive.

Hyenas and social intelligence in NYT

There's a pretty good article by Carl Zimmer in the New York Times about a hyena researcher who is comparing the brains of four different species of hyenas with different social structures to see if the prediction of a brain size-social complexity correlation holds in hyenas, as it supposedly does in primates.
I was glad to see that she was also testing other forms of intelligence such as figuring out how to get food out of a cage, but the two main hypotheses for large brains (social intelligence and ability to find/get food) are probably closely linked and hard to tease apart... but she might find that one hypothesis better fits the data on hyenas.