Monthly Archives: November 2015

The Genetic Cost of Neanderthal Introgression

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The Genetic Cost of Neanderthal Introgression

Kelley Harris, Rasmus Nielsen
bioRxiv doi: http://dx.doi.org/10.1101/030387

Approximately 2-4% of the human genome is in non-Africans comprised of DNA intro- gressed from Neanderthals. Recent studies have shown that there is a paucity of introgressed DNA around functional regions, presumably caused by selection after introgression. This observation has been suggested to be a possible consequence of the accumulation of a large amount of Dobzhansky-Muller incompatibilities, i.e. epistatic effects between human and Neanderthal specific mutations, since the divergence of humans and Neanderthals approx. 400-600 kya. However, using previously published estimates of inbreeding in Neanderthals, and of the distribution of fitness effects from human protein coding genes, we show that the average Neanderthal would have had at least 40% lower fitness than the average human due to higher levels of inbreeding and an increased mutational load, regardless of the dominance coefficients of new mutations. Using simulations, we show that under the assumption of additive dominance effects, early Neanderthal/human hybrids would have experienced strong negative selection, though not so strong that it would prevent Neanderthal DNA from entering the human population. In fact, the increased mutational load in Neanderthals predicts the observed reduction in Neanderthal introgressed segments around protein coding genes, without any need to invoke epistasis. The simulations also predict that there is a residual Neanderthal derived mutational load in non-African humans, leading to an average fitness reduction of at least 0.5%. Although there has been much previous debate about the effects of the out-of-Africa bottleneck on mutational loads in non-Africans, the significant deleterious effects of Neanderthal introgression have hitherto been left out of this discussion, but might be just as important for understanding fitness differences among human populations. We also show that if deleterious mutations are recessive, the Neanderthal admixture fraction would gradually increase over time due to selection for Neanderthal haplotypes that mask human deleterious mutations in the heterozygous state. This effect of dominance heterosis might partially explain why adaptive introgression appears to be widespread in nature.

Genome-wide association studies suggest limited immune gene enrichment in schizophrenia compared to six immune diseases

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Genome-wide association studies suggest limited immune gene enrichment in schizophrenia compared to six immune diseases

Jennie G Pouget, Vanessa F Goncalves, Schizophrenia Working Group of the PGC, Sarah L Spain, Hilary K Finucane, Soumya Raychaudhuri, James L Kennedy, Jo Knight
bioRxiv doi: http://dx.doi.org/10.1101/030411

There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia, and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes to schizophrenia. We show that there is no genome-wide enrichment of immune loci in the largest genetic study of schizophrenia conducted to date, in contrast to six diseases of known immune origin. Among 108 regions of the genome previously associated with schizophrenia, we identify six immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, non-immune roles in the brain. Our results suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes regulating brain development and plasticity. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they indicate a non-genetic etiology for immune processes that may be involved in schizophrenia. Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia.

Defining individual size in the model filamentous fungus Neurospora crassa

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Defining individual size in the model filamentous fungus Neurospora crassa
Linda Ma, Boya Song, Thomas Curran, Nhu Phong, Emilie Dressaire, Marcus Roper

Fungal mycelia potentially violate each of the tenets that define individuality in paradigmatic organisms: the mycelium of a filamentous fungi can contain millions of genetically diverse nuclei, each capable of founding new mycelia. Moreover a single mycelium can potentially stretch over kilometers and it unlikely that distant parts of these ultra-large mycelia share resources or have the same fitness. Here we directly measure how a single mycelium of the model ascomycete Neurospora crassa is patterned into reproductive individuals, by analyzing the genetic diversity of thousands of asexual spores to determine the size of the nuclear sub-population that produces each spore. In a mycelium with a single growth direction the entire width of the mycelium forms a single population. By contrast, mycelia with expanding frontiers fragment into approximately 1000 reproducing subpopulation per square cm. Nuclear subpopulations fragment further when the mycelial network is perturbed by either chemical or desiccation stress. Our results provide a concept of fungal individuality that is directly connected to reproductive potential, and therefore to theories of how fungal individuals adapt and evolve over time. Our data show that the size of fungal individuals is a dynamic and environment-dependent property, even within apparently totally connected fungal mycelia.

Multiple sequence alignment for short sequences

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Multiple sequence alignment for short sequences
Kristóf Takács

Multiple sequence alignment (MSA) has been one of the most important problems in bioinformatics for more decades and it is still heavily examined by many mathematicians and biologists. However, mostly because of the practical motivation of this problem, the research on this topic is focused on aligning long sequences. It is understandable, since the sequences that need to be aligned (usually DNA or protein sequences) are generally quite long (e. g., at least 30-40 characters). Nevertheless, it is a challenging question that exactly where MSA starts to become a real hard problem (since it is known that MSA is NP-complete [2]), and the key to answer this question is to examine short sequences. If the optimal alignment for short sequences could be determined in polynomial time, then these results may help to develop faster or more accurate heuristic algorithms for aligning long sequences. In this work, it is shown that for length-1 sequences using arbitrary metric, as well as for length-2 sequences using unit metric, the optimum of the MSA problem can be achieved by the trivial alignment.

Autocratic strategies for iterated games with arbitrary action spaces

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Autocratic strategies for iterated games with arbitrary action spaces
Alex McAvoy, Christoph Hauert

The recent discovery of zero-determinant strategies for the repeated Prisoner’s Dilemma sparked a surge of interest in the surprising fact that a player can exert control over iterated interactions regardless of the opponent’s response. These remarkable strategies, however, are known to exist only in games in which players choose between two alternative actions such as “cooperate” and “defect.” Here we introduce a broader class of autocratic strategies by extending zero-determinant strategies to iterated games with more general action spaces. We use the continuous Donation Game as an example, which represents an instance of the Prisoner’s Dilemma that intuitively extends to a continuous range of cooperation levels. Surprisingly, despite the fact that the opponent has infinitely many donation levels from which to choose, a player can devise an autocratic strategy to enforce a linear relationship between his or her payoff and that of the opponent even when restricting his or her actions to merely two discrete levels of cooperation throughout the course of the interaction. In particular, a player can use such a strategy to extort an unfair share of the payoffs from the opponent. Therefore, although the action space for the continuous Donation Game dwarfs that of the classical Prisoner’s Dilemma, players can still devise relatively simple autocratic and, in particular, extortionate strategies.