Exploring signatures of positive selection in pigmentation candidate genes in populations of East Asian ancestry

Hider, Jessica; Gittelman, Rachel M.; Shah, Tapan; Edwards, Melissa; Rosenbloom, Arnold; Akey, Joshua M.; Parra, Esteban J.

doi:10.1186/1471-2148-13-150

Cited by 60 publications

(56 citation statements)

References 71 publications

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“…Guided by the interactome dataset, we explored here the unique in vivo interactions between TPC isoforms and Rab GTPases, which we discovered impacted pigmentation and trafficking dynamics in the frog oocyte. Melanin pigmentation protects cells (including frog eggs) from UV damage, and it is noteworthy that TPCs (41) and interactors evidenced here (47) are linked in genetic association studies to pigmentation defects in humans, implying an evolutionarily conserved role. These phenotypes depend on TPC2 activity and correct localization of TPC2 within the cell.…”

Section: Discussionmentioning

confidence: 81%

The Two-pore channel (TPC) interactome unmasks isoform-specific roles for TPCs in endolysosomal morphology and cell pigmentation

Lin-Moshier

Keebler

Hooper

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

110

171

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The two-pore channels (TPC1 and TPC2) belong to an ancient family of intracellular ion channels expressed in the endolysosomal system. Little is known about how regulatory inputs converge to modulate TPC activity, and proposed activation mechanisms are controversial. Here, we compiled a proteomic characterization of the human TPC interactome, which revealed that TPCs complex with many proteins involved in Ca 2+ homeostasis, trafficking, and membrane organization. Among these interactors, TPCs were resolved to scaffold Rab GTPases and regulate endomembrane dynamics in an isoformspecific manner. TPC2, but not TPC1, caused a proliferation of endolysosomal structures, dysregulating intracellular trafficking, and cellular pigmentation. These outcomes required both TPC2 and Rab activity, as well as their interactivity, because TPC2 mutants that were inactive, or rerouted away from their endogenous expression locale, or deficient in Rab binding, failed to replicate these outcomes. Nicotinic acid adenine dinucleotide phosphate (NAADP)-evoked Ca 2+ release was also impaired using either a Rab bindingdefective TPC2 mutant or a Rab inhibitor. These data suggest a fundamental role for the ancient TPC complex in trafficking that holds relevance for lysosomal proliferative scenarios observed in disease. Ca 2+ signaling | lysosome | Xenopus T wo-pore channels (TPCs) are an ancient family of intracellular ion channels and a likely ancestral stepping stone in the evolution of voltage-gated Ca 2+ and Na + channels (1). Architecturally, TPCs resemble a halved voltage-gated Ca 2+ /Na + channel with cytosolic NH 2 and COOH termini, comprising two repeats of six transmembrane spanning helices with a putative pore-forming domain between the fifth and sixth membranespanning regions. Since their discovery in vertebrate systems, many studies have investigated the properties of these channels (2-7) that may support such a lengthy evolutionary pedigree. In this context, demonstration that (i) the two human TPC isoforms (TPC1 and TPC2) are uniquely distributed within the endolysosomal system (2, 3) and that (ii) TPC channel activity is activated by the Ca 2+ mobilizing molecule nicotinic acid adenine dinucleotide phosphate (NAADP) (4-6) generated considerable excitement that TPCs function as effectors of this mercurial second messenger long known to trigger Ca 2+ release from "acidic stores." The spectrum of physiological activities that have been linked to NAADP signaling over the last 25 years (8, 9) may therefore be realized through regulation of TPC activity. However, recent studies have questioned the idea that TPCs are NAADP targets (10, 11), demonstrating instead that TPCs act as Na + channels regulated by the endolysosomal phosphoinositide PI(3,5)P 2 . Such controversy (12, 13) underscores how little we know about TPC regulatory inputs and the dynamic composition of TPC complexes within cells.Here, to generate unbiased insight into the cell biology of the TPC complex, we report a proteomic analysis of human TPCs. The TPC interactom...

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Section: Discussionmentioning

confidence: 81%

The Two-pore channel (TPC) interactome unmasks isoform-specific roles for TPCs in endolysosomal morphology and cell pigmentation

Lin-Moshier

Keebler

Hooper

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

110

171

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“…Since a selected mutation usually spreads rapidly and less time is available for recombination, the genetic diversity around a positively selected site is commonly expected to decrease, a phenomenon called a selective sweep (Smith and Haigh 1974;Nielsen 2005). Most statistics used to detect genetic signatures of positive selection rely on this assumption (Tajima 1989;Fu and Akey 2013;Hider et al 2013;. We show that these signatures are reversed in slow sweeps/selective strolls, with increased genetic diversity compared to that of a neutrally fixing allele.…”

mentioning

confidence: 84%

Selective Strolls: Fixation and Extinction in Diploids Are Slower for Weakly Selected Mutations Than for Neutral Ones

Mafessoni

Lachmann

2015

Genetics

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In finite populations, an allele disappears or reaches fixation due to two main forces, selection and drift. Selection is generally thought to accelerate the process: a selected mutation will reach fixation faster than a neutral one, and a disadvantageous one will quickly disappear from the population. We show that even in simple diploid populations, this is often not true. Dominance and recessivity unexpectedly slow down the evolutionary process for weakly selected alleles. In particular, slightly advantageous dominant and mildly deleterious recessive mutations reach fixation slightly more slowly than neutral ones (at most 5%). This phenomenon determines genetic signatures opposite to those expected under strong selection, such as increased instead of decreased genetic diversity around the selected site. Furthermore, we characterize a new phenomenon: mildly deleterious recessive alleles, thought to represent a wide fraction of newly arising mutations, on average survive in a population slightly longer than neutral ones, before getting lost. Consequently, these mutations are on average slightly older than neutral ones, in contrast with previous expectations. Furthermore, they slightly increase the amount of weakly deleterious polymorphisms, as a consequence of the longer unconditional sojourn times compared to neutral mutations.KEYWORDS weak selection; diffusion approximation; dominance; recessive mutations A new allele emerging in a finite population usually has two possible fates-extinction or fixation. Selection affects the probability with which these occur and how long it will take. Thus, an advantageous allele has an increased chance to fix, due to positive selection, while a deleterious mutation has an increased chance of extinction. In both cases, the time until fixation and extinction is commonly thought to decrease with the strength of selection (Kimura and Ohta 1969b;van Herwaarden and Van Der Wal 2002). Kimura and Ohta (1969a,b) and Ewens (2004) applied diffusion theory to model finite populations, obtaining keystone approximations for the neutral case, in the absence of selection, or when selection is fairly strong. Recently it has been pointed out that in haploid models, in the presence of frequency-dependent fitness, the time to fixation of a positively selected allele can increase with the strength of selection (Altrock et al. 2010(Altrock et al. , 2012. In diploids, a newly arising mutation is usually expected to have a time to fixation longer than that of a neutral one in the case of overdominance, when the heterozygote has an higher fitness than the two homozygotes-a case usually referred to as heterozygote advantage or more generally balancing selection (Key et al. 2014). In the case of overdominance, both alleles would be maintained in an infinite population. In this article we unify these results, showing that in diploids, certain classes of mutations behave as slow sweeps/selective strolls: the time to fixation of a positively selected allele A can be slightly longer than in the...

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“…The overrepresentation in the pigmentation category is the result of amino acid substitutions in two genes involved in melanosome function (GPR143 and LYST), for which the derived alleles are at high frequency in Africa and fixed outside Africa. These mutations may contribute to differences in pigmentation among present-day humans (22,23). In contrast, the behavioral category is the result of substitutions that seem to be fixed in all present-day humans and occur in the three genes adenylosuccinate lyase (ADSL), glycine dehydrogenase (GLDC), and transmembrane protein SLITRK1.…”

Section: Significancementioning

confidence: 99%

Patterns of coding variation in the complete exomes of three Neandertals

Castellano

Parra

Sánchez-Quinto

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

235

230

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We present the DNA sequence of 17,367 protein-coding genes in two Neandertals from Spain and Croatia and analyze them together with the genome sequence recently determined from a Neandertal from southern Siberia. Comparisons with present-day humans from Africa, Europe, and Asia reveal that genetic diversity among Neandertals was remarkably low, and that they carried a higher proportion of amino acid-changing (nonsynonymous) alleles inferred to alter protein structure or function than present-day humans. Thus, Neandertals across Eurasia had a smaller long-term effective population than present-day humans. We also identify amino acid substitutions in Neandertals and present-day humans that may underlie phenotypic differences between the two groups. We find that genes involved in skeletal morphology have changed more in the lineage leading to Neandertals than in the ancestral lineage common to archaic and modern humans, whereas genes involved in behavior and pigmentation have changed more on the modern human lineage.ancient DNA | exome capture | site frequency spectra | paleogenetics A nalyses of the coding regions of multiple present-day human individuals have uncovered many amino acid-changing SNPs segregating at low frequency in present-day human populations (1-7). It also has been shown that Europeans carry a larger proportion than Africans of amino acid-changing SNPs inferred to alter the structure or function of proteins and thus to be potentially deleterious (4), a fact attributed to the bottleneck and subsequent expansion of human populations during and after the migration out of Africa (4). In contrast, little is known about the coding variation in Neandertals, an extinct hominin group closely related to presentday humans. The main reasons for this are the rarity of Neandertal remains and the fact that >99% of the DNA extracted from typical Neandertal bones is derived from microbes (8, 9), making shotgun sequencing of the endogenous DNA impractical.Here, we use a hybridization approach to enrich and sequence the protein-coding fractions of the genomes of two Neandertals from Spain and Croatia. We analyze them together with the genome sequence recently determined from a Neandertal from southern Siberia (10) and show that the genetic diversity, pattern of coding variation, and genes that may underlie phenotypic changes in Neandertals are remarkably different from those in present-day humans. Results and DiscussionWe used densely tiled oligonucleotide probes (9) and a recently described protocol (11) to capture the protein-coding exons from 17,367 genes in a ∼49,000-y-old (12) (uncalibrated radiocarbon date) Neandertal from Spain (SD1253, El Sidrón Cave) and a ∼44,000-y-old (uncalibrated radiocarbon date) Neandertal from Croatia (Vi33.15, Vindija Cave). The DNA libraries from these two Neandertals contain 0.2% and 0.5% endogenous DNA, respectively, and the capture approach enriched the endogenous DNA 325-fold and 153-fold, resulting in an average coverage of 12.5-fold and 42.0-fold for the El Sidrón and Vindi...

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Exploring signatures of positive selection in pigmentation candidate genes in populations of East Asian ancestry

Cited by 60 publications

References 71 publications

The Two-pore channel (TPC) interactome unmasks isoform-specific roles for TPCs in endolysosomal morphology and cell pigmentation

The Two-pore channel (TPC) interactome unmasks isoform-specific roles for TPCs in endolysosomal morphology and cell pigmentation

Selective Strolls: Fixation and Extinction in Diploids Are Slower for Weakly Selected Mutations Than for Neutral Ones

Patterns of coding variation in the complete exomes of three Neandertals

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