Update II: This comment sums up the pertinent issues.
Update: Please see comments below. This may be an infectious disease story, and not a genetic one.
When a reader sent me an email about the story, I assumed it was a rather sophisticated hoax. The short of it is that an 11 year old boy, Colman Chadam, has been pulled out of his school in Palo Alto because he carries alleles for cystic fibrosis, though he is asymptomatic (i.e., he has never manifested any symptoms of c.f.) administrators are worried that he might pose a risk to some students who do show progression of c.f. (bacterial infections can spread from child to child). As you probably know about 1 out of 30 people of European descent is a carrier for one of the many thousands of mutant variants for cystic fibrosis. The details of Colman Chadam’s results are not totally clear. Is he just a carrier? Or does he have two copies of cystic fibrosis, but somehow they differ enough that they can functionally complement each other?
We don’t know. But we do know that the lawyer from the school, Lenore Silverman, has stated that “The district is not willing to risk a potentially life-threatening illness among kids.” The risk here is non-existent. Not to be creepy, but does the school require that people with various venereal diseases also avoid the premises? With the small, but non-trivial, frequency of sexual abuse at school they too post a illness risk to the kids. In fact, more than Colman Chadam.
You can read everything at The San Francisco Chronicle. Perhaps you want to contact some of the staff at Jordan Middle School in Palo Alto. These people should be ashamed of themselves. I know we live in a litigious society, and being in education isn’t the easiest job, but we deserve better than this!
Rice is a pretty big deal. There’s really no need to justify research on this crop. It feeds literally billions, so the funding will always flow. Would that we knew rice as well as we know C. elgans. After yesterday’s travesty of a paper on barley I thought that readers might find a new paper in Nature, A map of rice genome variation reveals the origin of cultivated rice, more interesting and illuminating. The authors used genomic sequencing, of varied coverage (i.e., very deep, repeated, and therefore accurate coverage vs. a single pass which is a very rough draft), to assess the relationship between Asian wild rice and two of the dominant domestic cultivars, indica (long-grain paddy rice) and japonica (short-grain dry cultivation rice). Presumably the two cultivars derive from a wild ancestor, but the details are still being hashed out.
I’ve mentioned a few times that the Reich lab has been finding suggestive evidence for admixture between indigenous South Asians and a West Eurasian group on the order of ~3,000 years before the present. The modal explanation is probably an Indo-Aryan intrusion. Dienekes used rolloff in ADMIXTOOLS to repeat these general findings. Specifically, he found signal for an admixture event analogous to one between non-Brahmin South Indians and Northern Europeans. I say analogous because I do not mean to imply that the admixture was exactly of this form. Rather, there are general resemblances in the genetic profiles across the four groups (i.e., Orcadian & North Kannadi, and population X and Y which merged to form South Indian Brahmins).
Dr. Joseph Pickrell has updated his preprint, The genetic prehistory of southern Africa, with some more material on the Sandawe. I’ve explored the genetics of the Sandawe a bit using ADMIXTURE, so I jumped straight to the section on ROLLOFF:
…To further examine this, we turned to ROLLOFF. We used Dinka and French as representatives of the mixing populations (since date estimates are robust to improperly specified reference populations). The results are shown in Supplementary Figure S22. Both populations show a detectable curve, though the signal is much stronger in the Sandawe than in the Hadza. The implied dates are 89 generations (2500 years) ago for the Hadza and 66 generations (2000 years) ago for the Sandawe. These are qualitatively similar signals to those seen by Pagani et al.  in Ethiopian populations. There are two possible historical scenarios that could lead to these signals: either the Hadza and Sandawe both directly admixed with a western Eurasian population about 2,000 years ago, or they admixed with an east African population that was itself admixed with a western Eurasian population. The latter possibility would be consistent with known east African admixture into the Sandawe  .
One of the weird things about genetics is that it encompasses both the abstract and the concrete. The formal and physical. You can talk to a geneticist who is mostly interested in details of molecular mechanisms, and is steeped in structural biology. For these people genes are specific and material things. In contrast there are other geneticists who focus more on genes as units of analysis. In this case genes are semantic labels for the mediators within an intersection of phenomena. Recall that genetics predates the knowledge of its concrete substrate by 50 years! By the 1920s Mendelian genetics had been fused with evolutionary biology to create a systematic framework in which we could understand the patterns of inheritance across the generations. In the 1950s the DNA revolution was upon us, but as W. D. Hamilton recalls this had only a minimal impact on the evolutionary genetic thinkers of the era. With the Lewontin and Hubby allozyme paper in the mid-1960s this sort of benign disciplinary evasion was no longer possible; the field of molecular evolution came into its own.*
Today with genomics these human-imposed artificialities are fading away. Consider the concept of genetic recombination. Originally an abstraction in a formal Mendelian system, today it is of great interest to molecular biologists who are curious as to its exact mechanism and purpose, and genomicists who are interested in the constraints upon the phenomenon due to its physical parameters (e.g., recombination hotspots). If we were to discover alien beings I assume that there would be some sort of genetics in an abstract sense. But would they package their genes in chromosomes? Would their complex organisms tend toward dioecy? I wouldn’t be surprised if the genetics of alien species have their own particular kinks subject to the contingent nature of the physical scaffolding of the process.
There’s been a mild debate in the literature about the human mutation rate recently. I assume it will reach some consensus within the next few years, but until then Nature Reviews Genetics has published something which lays out the implications in precise fashion for a slower mutation rate. Revising the human mutation rate: implications for understanding human evolution:
The four key points may be summarized as follows. First, the divergence between modern humans and both Neanderthals and Denisovans, which was originally estimated to be 272,000–435,000 years ago, is revised to 400,000–600,000 years ago. This is in better agreement with the range of estimated split times from mtDNA and also with the idea that the ancestral population of these groups may have been H. heidelbergensis. Second, for the split between the Khoe–San and other modern humans, revised estimates from nuclear genomic data suggest a divergence 250,000–300,000 years ago, older than single-locus estimates for the root of the human tree. Third, revised estimates of the separation time between Africans and non-Africans suggest that this predates the appearance of modern humans in Europe and Asia by up to 60,000 years. We have suggested a scenario of exodus from Africa via an intermediate population in East Africa and the Middle East, which may fit better with growing evidence for modern human occupation of the latter region before the wider colonization of Eurasia and may provide a longer interval for Neanderthal admixture with non-African populations. Finally, revised split times of 40,000–80,000 years ago for Europeans and Asians agree better with the palaeoanthropological record and with estimates from mtDNA.
The authors do understand that their phylogenetic model impacts their inferences. If there was a lot of archaic admixture into the Khoe and Bushmen their divergence from other modern humans might be inflated. But it is always striking to me that there is this strange result that populations like the Yoruba might be in a clade with non-Africans against Khoe and Bushmen.
I spend some time thinking about genetic architecture. If you read media accounts of genetics you wouldn’t know there was such a thing. Why not? Because it makes a narrative rather messy and complex. Rather, a better story is one where you have a gene-for-something. But the gene-for-something model is probably most useful in the domain of recessive diseases. In these cases you have a mutant variant which has a powerful effect when found in two copies in an individual. The distinction between the disease state and the “wild” state is rather straightforward. Not so with many “complex traits.”
Two papers came into my RSS feed which illustrate two ends of this dynamic. First, A Sexual Ornament in Chickens Is Affected by Pleiotropic Alleles at HAO1 and BMP2, Selected during Domestication:
The genetic analysis of phenotypes and the identification of the causative underlying genes remain central to molecular and evolutionary biology. By utilizing the domestication process, it is possible to exploit the large differences between domesticated animals and their wild counterparts to study both this and the mechanism of domestication itself. Domestication has been central to the advent of modern civilization; and yet, despite domesticated animals displaying similar adaptations in morphology, physiology, and behaviour, the genetic basis of these changes are unknown. In addition, though sexual selection theory has been the subject of a vast amount of study, very little is known about which genes are underpinning such traits. We have generated multiple intercrosses and advanced intercrosses based on wild-derived and domestic chickens to fine-map genomic regions affecting a sexual ornament. These regions have been over-laid with putative selective sweeps identified in domestic chickens and found to be significantly associated with them. By using expression QTL analysis, we show that two genes in one region, HAO1 and BMP2, are controlling multiple aspects of the domestication phenotype, from a sexual ornament to multiple life history traits. This demonstrates the importance of pleiotropy (or extremely close linkage) in controlling these genetic changes.
A nice elegant solution. Strong bout of selection, and a response on two genes, which also generates a lot of side effect phenotypes. This section in particular intrigued me:
One of the more fascinating things about getting much of your child’s pedigree genotyped is that one can ascertain true relatedness to various relatives, rather than just expected relatedness. For example, 28% of her genome is identical by descent from my father, while 22% is from my mother. She is 26% identical by descent with one uncle, and 24% with another. More practically, the understanding of patterns realized and concrete genetic relatedness within families allows us another avenue into teasing apart heritability. Though this method has been around for more than half-a-decade, I find it curious that when I post on it some commenters immediately make objections to twin studies. Why? Because they assume that the analysis had to be a twin study because they don’t know of the genomic methodology!
But on a broader evolutionary scale, does this matter? Two of my siblings have a relatedness of 41%. In other words, as you can see in the histogram there is a wide variation in relatedness. Might this perhaps impact social relations? One can imagine genetically more similar siblings aligning against those who are dissimilar. Or not. I am skeptical that this would apply to humans, but I do wonder about organisms with larger broods. If we don’t find much variation on the scale of siblings, despite genetic variation (and therefore, likely phenotypic tells of similarity), then I would hazard to suggest that inclusive fitness is not quite the razor sharp discerning tool that some posit it is. Rather, it is part of the broader swiss army knife of behavioral ecology.
The map to the right shows the frequencies of HGDP populations on SLC45A2, which is a locus that has been implicated in skin color variation in humans. It’s for the SNP rs16891982, and I yanked the figure from IrisPlex: A sensitive DNA tool for accurate prediction of blue and brown eye colour in the absence of ancestry information. Brown represents the genotype CC, green CG, and blue, GG. Europeans who have olive skin often carry the minor allele, C. While SLC24A5 is really bad at distinguishing West Eurasians from each other, SLC45A2 is better. Though both are fixed in Northern Europe, the former stays operationally fixed in frequency outside of Europe, in the Near East. As I stated earlier the proportions of the ancestral SNP in the Middle Eastern populations in the HGDP seem to be easily explained by the Sub-Saharan admixture you can find in these groups.
In contrast major SNPs in SLC45A2 are closer to disjoint between Europeans and South Asians. For example I’m a homozygote for the C allele. And yet even here we need to be careful. I want in particular to draw your attention to the frequencies in the Middle Eastern populations, the Sardinians, and the Kalash of Pakistan.
The Kalash, and their Nuristani cousins, have often been observed to have “European” physical features. These populations even trade in legends of descent from the Macedonians of Alexander. And the genetics here shows why. Though the Kalash far are more closely related to other Northwest South Asians than to Europeans, on the subset of genes which are implicated in pigmentation many of them could actually “pass” for Europeans. In fact, it is interesting to me that by these measures the Sardinians are no more European than groups like the Kalash and the Druze (in contrast to the total genome, where Sardinians may be the best reference for Western Europeans). They have a lower frequency of the SNP strongly associated with blue eyes than either of these groups, for example.
In the above paper they also produced a chart which illustrated the relationships of HGDP populations as a measure only of the six SNPs they used in their prediction method. These are markers which distinguish blue and brown eye color in Europeans efficiently.
|Spatial linguistic variation||Spatial genetic variation||Temporal linguistic variation||Temporal genetic variation|
|Modern Age||Very low||Low||Low||Moderate-to-low|
In the comments below I posited a scenario to explain a strange inference from a paper from a few years back, Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude:
Population historical models were estimated (8) from the two-dimensional frequency spectrum of synonymous sites in the two populations. The best-fitting model suggested that the Tibetan and Han populations diverged 2750 years ago, with the Han population growing from a small initial size and the Tibetan population contracting from a large initial size (fig. S2). Migration was inferred from the Tibetan to the Han sample, with recent admixture in the opposite direction.
2,750 years would place the divergence of modern Tibetans and Chinese a few hundred years before Confucius. In fact, it would technically post-date the first historically attested Chinese writing, from the Shang dynasty. This result was pretty incredible, though one of the main authors believes it is a reasonable estimate. There are many ways you can explain this sort of divergence time, but one way which I elucidated below is rather simple. Imagine, if you will, a large set of populations which are culturally very distinct, but engage in gene flow with each other. This is not a preposterous scenario. Because of the restrictions on the manner in which genes are inherited, and the flexibility of cultural traits in terms of transmission, you often have situations where change in allele frequency is clinal while change in culturae is punctuated. To give a concrete example, moving along a transect on the North European plain will result in a gradual change in allele frequencies, but a crisper shift in languages spoke. The two are not totally distinct. Allele frequencies will tend to shift more at language boundaries, but whereas most of the difference is between groups across languages, in relation to genes usually the differences are within groups.
Sometimes when you read reviews or papers you need to look very closely at what people say in a tentative speculative fashion. That’s because though the prose may be as such when read plainly and without context, you often have more prior information as to the background of the authors. In other words, assertions which literally seem cautious are actually foreshadowing likely probabilities down the pipeline, because the authors are not distant third-party observers, but active participants in the production of new insights. I think that’s what’s going on in a new paper in Trends in Genetics, The genetic history of Europeans:
Future research should also reveal the effects of post-Neolithic demographic processes, including migration events, which preliminary data suggest had a major impact upon the distribution of genetic variation. These include events associated with Bronze Age civilizations, Iron Age cultures, and later migrations, including those triggered by the rise and fall of Empires. Challenges remain in being able to sequence aDNA routinely from serial samples in the range of megabases, and in the development of software that allows spatially-explicit simulation of genome-scale data, but advances in these areas are now a weekly occurrence and the stage is set for a rapid increase in our knowledge on the evolutionary history of AMH in Europe.
I’d have said this was crazy a few years ago. No longer.
In many ways the image of Africa in the minds of Westerners has become a trope. The “Dark Continent,” eternal, and primal. Like many tropes the realized existence of this Africa is only within the imagination. The real Africa is far different. For there is no real Africa, there Africas. This truth is on my mind this week as two papers of great importance in understanding African genetic history finally saw the light of day. First, Dr. Joseph Pickrell et al. posted their preprint, The genetic prehistory of southern Africa, to arXiv. Second, out of the Tishkoff lab came Evolutionary History and Adaptation from High-Coverage Whole-Genome Sequences of Diverse African Hunter-Gatherers. Let me step aside here and observe a secondary, but non-trivial, detail. The former is an open access preprint. The second is a complete paper published in a relatively high impact journal, Cell, for which the paper itself does not seem typical or appropriate. This is fair enough, most people do not read journals front to back in this day. But unlike Dr. Joseph Pickrell’s paper the paper in Cell is paywalled, and from what I can tell you can not obtain the supporting information without getting beyond the gate! So if you need that paper, email me and I will send it onward (I would just post it on a server, but I’ve gotten nasty emails from the legal departments of publishers, so I am wary of doing that).
Research shows that the descendants of people who in 1858 had “rich” surnames such as Percy and Glanville, indicating they were descended from the French nobility, are still substantially wealthier in 2011 than those with traditionally “poor” or artisanal surnames. Artisans are defined as skilled manual workers.
As Steve Sailer observes strict adherence to surnames on a mass scale post-dates the Norman invasion by centuries. So the headline is pretty sensational. But I went and read the original working paper, and there is no mention of Norman or French names! The author of the piece in The Telegraph is probably right (i.e., a casual reading of history will show that Norman names are enriched in the English elite), but this is clearly another case of one having to be careful of the details when it comes to British media.
To the left is a panel from a new paper in PLoS Genetics, Selection-Driven Gene Loss in Bacteria. The y-axis is selection, so above 0 represents a positive selection coefficient, and below a negative one. The lineages above the x-axis then are more fit against the baseline wild type (selection coefficients above 0.01 can be considered rather strong, with 0.08 very strong). The top-line result of this paper is that 11 out of 55 deletion constructs in bacterial lineages seem to result in increased fitness. This is rather weird if you are viewing it from a homocentric perspective, or more ecumenically, a multicelluar organismic perspective. If you add copies of a gene the result is not always good because of dosage effects (Down Syndrome is an extreme case of this on the smallest chromosome). If you delete whole regions of the genome the results are usually disastrous. This comports with common sense. If you break something it isn’t usually a good thing. It was there for a reason.
But this heuristic may not be applicable to bacteria. Or, more precisely, when you remove the large set of parameters which constrain the adaptive landscape of multicellular organisms, you may be exploring an evolutionary space with somewhat different rules. If someone reported that 25% of deletions in a multicellular organism resulted in increased fitness I’d probably be curious if there was a basic human error somewhere along the way generating this crazy proportion. But fast-breeding and genomically economically designed bacteria may not be governed by the same expectations.
In conclusion, we propose that the ancestral H2′ haplotype arose in eastern or central Africa and spread to southern Africa before the emergence of anatomically modern humans…Approximately 2.3 million years ago, the inversion rearranged to what we now refer as the direct orientation haplotype (H1′). This haplotype spread throughout the Homo ancestral populations in the African continent, virtually replacing the H2′ haplotype and becoming the predominant haplotype. We note that both the Denisova and Neandertal sister groups are predicted to have H1′ haplotypes…These early haplotypes were much simpler in their duplication architecture, similar to the patterns seen in great apes. We find that the more complex duplication architectures are particularly enriched in populations that migrated out of Africa. On the basis of sequence at the duplication loci, we estimate that the H2-specific duplication event occurred approximately 1.3 million years ago. Independent of the H2 duplication, the H1-specific duplication event occurred much more recently, approximately 250,000 years ago. Notably, we did not observe this haplotype in any of the African or Asian populations studied, suggesting that it may have been lost in these groups as a result of genetic drift. The H2D haplotype has risen to frequencies of 10–25% in European populations with virtually no genetic variation, suggesting an extremely recent and rapid expansion of this haplotype. High-coverage sequencing of more individuals along with fecundity data will likely shed further light on whether the high frequency of the haplotype-specific duplication in Europeans is due to selection or the effects of demographic history specific to this locus.
H2D individuals are susceptible to disease. If there is a fitness gain, there is also a loss. Despite his eugenical enthusiasms W. D. Hamilton ultimately gave up on the idea because he admitted it was difficult to predict what was beneficial and what is deleterious. Context matters. The distribution of haplotypes in this region seems to reflect echoes of deep pre-”Out of Africa” history in our species.
Rosie Redfield has an opinion piece out in PLoS Biology on refashioning genetics education for the 21st century, “Why Do We Have to Learn This Stuff?”—A New Genetics for 21st Century Students:
…Genetic analysis used to be the most powerful tool for understanding how organisms work, and thus the best skill we could give our students, but its research role has been largely supplanted by molecular methods. Cuts to genetic analysis also threaten the problem-based learning that has been a hallmark of genetics courses. Genetics instructors have all devoted time to developing problems that replicate those arising in real genetics research labs, and a major feature in textbook choice is the quantity and quality of the end-of-chapter problems.
Other cuts will be less traumatic. Our students will probably never need to do a 3-factor cross, except maybe in an outdated genetics laboratory course, nor to analyze phenotypic ratios of progeny, once “one of the pillars of genetics”…There’s also little justification for retaining haploid genetics, fungal genetics, tetrad analysis, and classical somatic-cell genetics in an introductory genetics course. Classical bacterial genetics (conjugation, transduction, transformation) should go too—I’m a bacterial geneticist, so trust me on this one.
Thoughts? Recently had a discussion whether phylogeneticists considered themselves geneticists (qualified “no”). Quantitative genetics really evolved out of biometrics, which actually opposed Mendelian genetics. You can construct quantitative genetics from Mendelian first principles, but it is not necessary. As for population vs. molecular, ask each group what they mean by “gene.” Modern developmental geneticists seem to be closely aligned with molecular geneticists.
I am not particularly mystical or sentimental about genetics. I favor openness. But I just started getting my daughter’s results back from 23andMe, and some of her coefficients of relatedness to her grandparents deviated sharply from 0.25. As I have blogged about this possibility I was obviously aware of the abstract probability here; but it is a different thing altogether to be faced with reality. How exactly does one go about explaining that one of your parents is ~50% closer genetically to their grandchild than the other? I don’t think it matters really in a concrete sense for them, but divulging this information makes me somewhat uncomfortable. Many, many, others are going to be confronted with these issues. We don’t have social norms yet. This isn’t cut & dried like paternity. Thoughts?
Well, almost no one:
“The unspoken central reason for the societal taboo and the penal ban on incest is the possibility of hereditary defects — a factor that Strasbourg only hinted at. But the intention behind the eugenic argument is one that is indefensible, and not just in Germany with its terrible Nazi past: The increased risk of hereditary defects does not justify a legal ban. Otherwise you would have to legally ban other risk groups, like women over 40 or people with genetic diseases, from having children. Does anyone truly want to prevent predictable disabilities using penal measures and thus deny disabled children the right to life in 2012? That’s absurd. And yet such fears of genetic damage are precisely what shape the punishibility of sexual intercourse between siblings.”
There are a set of arguments against near relation incest which strike me as generally ad hoc. And there’s social science to back that up. Incest is reflexively disgusting to most people (depending on how it is categorized). But disgust alone is not a sufficient grounds for banning a practice in educated circles today, so people create rationales after the fact. David Hume would not be surprised.
A few people have forwarded me this paper, Identification of common variants associated with human hippocampal and intracranial volumes:
…Whereas many brain imaging phenotypes are highly heritable…identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7).
Look at the sample sizes. Beware of behavior genomics with small sample sizes. Paul Thompson, one of the many authors of this paper, is giving media interviews. To me that’s a good sign, as he’s a very smart guy. He has some confidence in this study. Here’s the section which is resulting in the forwards:
… In addition, the C allele of rs10784502 is associated, on average, with 9,006.7 mm3 larger intracranial volume, or 0.58% of intracranial volume per risk allele and is weakly associated with increased general intelligence by approximately 1.29 IQ points per allele.
I’m a homozygote for the T allele for what it’s worth. But that’s not surprising. Look at the population distribution of the C allele from the HapMap: