Publications (20)115.06 Total impact
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Article: Interactions between serotonin transporter gene haplotypes and quality of mothers' parenting predict the development of children's noncompliance.
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ABSTRACT: The LPR and STin2 polymorphisms of the serotonin transporter gene (SLC6A4) were combined into haplotypes that, together with quality of maternal parenting, were used to predict initial levels and linear change in children's ( N = 138) noncompliance and aggression from age 18–54 months. Quality of mothers' parenting behavior was observed when children were 18 months old, and nonparental caregivers' reports of noncompliance and aggression were collected annually from 18 to 54 months of age. Quality of early parenting was negatively related to the slope of noncompliance only for children with the LPR-S/STin2-10 haplotype and to 18-month noncompliance only for children with haplotypes that did not include LPR-S. The findings support the notion that SLC6A4 haplotypes index differential susceptibility to variability in parenting quality, with certain haplotypes showing greater reactivity to both supportive and unsupportive environments. These different genetic backgrounds likely reflect an evolutionary response to variation in the parenting environment. (PsycINFO Database Record (c) 2012 APA, all rights reserved)Developmental Psychology 04/2012; 48(3):740-754. · 3.21 Impact Factor -
Article: Numb regulates Notch1, but not Notch3, during myogenesis.
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ABSTRACT: In the vertebrate embryo, skeletal muscle is derived from the myotome of the somites. Notch1-3 demonstrate overlapping and distinct expression patterns in mouse somites. Notch1 and Notch2 have been shown to be inhibitors of skeletal myogenesis. The current data demonstrate that Notch3 also is an effective inhibitor of MyoD induced myogenesis. Numb, an adaptor protein that promotes Notch degradation by recruiting the E3 ubiquitin ligase, Itch, is limited in expression to dividing cells of the dorsal medial lip of the dermomyotome and the myotome itself. Here the specificity of the four protein isoforms of Numb for the Notch receptors was examined. In transcription and myogenic differentiation assays, Notch1 was consistently negatively regulated by all four Numb isoforms, and Notch3 was not a target for Numb. Notch2 however was variably affected. Subsequent analyses showed that unlike Notch1, that Notch3 was not polyubiquitinated, nor degraded when co-expressed in cells with Numb. These data provide the first observations that Notch receptors are variably affected by Numb and will be important for the interpretation of the function of Notch and Numb interactions during the development of many different cells and tissues.Mechanisms of development 02/2011; 128(5-6):247-57. · 2.83 Impact Factor -
Article: Comparative vertebrate evolutionary analyses of type I collagen: potential of COL1a1 gene structure and intron variation for common bone-related diseases.
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ABSTRACT: Collagen type I alpha 1 (COL1a1), which encodes the primary subunit of type I collagen, the main structural and most abundant protein in vertebrates, harbors hundreds of mutations linked to human diseases like osteoporosis and osteogenesis imperfecta. Previous studies have attempted to predict the phenotypic severity associated with type I collagen mutations, yet an evolutionary analysis that compares historical and recent selective pressures, including across noncoding regions, has never been conducted. Here, we use a comparative genomic and species evolutionary analysis representing ∼450 My of vertebrate history to investigate functional constraints associated with both exons and introns of the >17-kb COL1a1 gene. We find that although the COL1a1 amino acid sequence is highly conserved, there are both spatial and temporal signatures of varying selective constraint across protein domains. Furthermore, sites of high evolutionary constraint significantly correlate with the location of disease-associated mutations, the latter of which also cluster with respect to specific severity classes typically categorized in clinical studies. Finally, we find that COL1a1 introns are significantly short in length with high GC content, patterns that are shared across highly diverged vertebrates, and which may be a signature of strong stabilizing selection for high COL1a1 gene expression. In conclusion, although previous studies focused on COL1a1 coding regions, the current results implicate introns as areas of high selective constraint and targets of bone-related phenotypic variation. From a broader perspective, our comparative evolutionary approach provides further resolution to models predicting mutations associated with bone-related function and disease severity.Molecular Biology and Evolution 01/2011; 28(1):533-42. · 5.55 Impact Factor -
Article: Haplotype structure and divergence at human and chimpanzee serotonin transporter and receptor genes: implications for behavioral disorder association analyses.
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ABSTRACT: Genetic variation in the human serotonin system has long-been studied because of its functional consequences and links to various behavior-related disorders and it being routinely targeted in research and development for drug therapy. However, aside from clinical studies, little is known about this genetic diversity and how it differs within and between human populations with respect to haplotype structure, which can greatly impact phenotype association studies. In addition, no evolutionary approach among humans and other primates has examined how long- and short-term selective pressures explain existing serotonin variation. Here, we examine DNA sequence variation in natural population samples of 192 human and 40 chimpanzee chromosome sequences for the most commonly implicated approximately 38-kb serotonin transporter (SLC6A4) and approximately 63-kb serotonin 2A receptor (HTR2A) genes. Our comparative population genetic analyses find significant linkage disequilibrium associated with functionally relevant variants in humans, as well as geographic variation for these haplotypes, at both loci. In addition, although amino acid divergence is consistent with purifying selection, promoter and untranslated regions exhibit significantly high divergence in both species lineages. These evolutionary analyses imply that the serotonin system may have accumulated significant regulatory variation over both recent and ancient periods of time in both humans and chimpanzees. We discuss the implications of this variation for disease association studies and for the evolution of behavior-related phenotypes during the divergence of humans and our closest primate relatives.Molecular Biology and Evolution 07/2010; 27(7):1518-29. · 5.55 Impact Factor -
Article: Different selective pressures shape the molecular evolution of color vision in chimpanzee and human populations.
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ABSTRACT: A population genetic analysis of the long-wavelength opsin (OPN1LW, "red") color vision gene in a global sample of 236 human nucleotide sequences had previously discovered nine amino acid replacement single nucleotide polymorphisms, which were found at high frequencies in both African and non-African populations and associated with an unusual haplotype diversity. Although this pattern of nucleotide diversity is consistent with balancing selection, it has been argued that a recombination "hot spot" or gene conversion within and between X-linked color vision genes alone may explain these patterns. The current analysis investigates a closely related primate with trichromatism to determine whether color vision gene amino acid polymorphism and signatures of adaptive evolution are characteristic of humans alone. Our population sample of 56 chimpanzee (Pan troglodytes) OPN1LW sequences shows three singleton amino acid polymorphisms and no unusual recombination or linkage disequilibrium patterns across the approximately 5.5-kb region analyzed. Our comparative population genetic approach shows that the patterns of OPN1LW variation in humans and chimpanzees are consistent with positive and purifying selection within the two lineages, respectively. Although the complex role of color vision has been greatly documented in primate evolution in general, it is surprising that trichromatism has followed very different selective trajectories even between humans and our closest relatives.Molecular Biology and Evolution 11/2008; 25(12):2735-43. · 5.55 Impact Factor -
Chapter: Malarial Resistance and Susceptibility, Genetics of
07/2008; , ISBN: 9780470015902 -
Article: Signatures of functional constraint at aye-aye opsin genes: the potential of adaptive color vision in a nocturnal primate.
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ABSTRACT: While color vision perception is thought to be adaptively correlated with foraging efficiency for diurnal mammals, those that forage exclusively at night may not need color vision nor have the capacity for it. Indeed, although the basic condition for mammals is dichromacy, diverse nocturnal mammals have only monochromatic vision, resulting from functional loss of the short-wavelength sensitive opsin gene. However, many nocturnal primates maintain intact two opsin genes and thus have dichromatic capacity. The evolutionary significance of this surprising observation has not yet been elucidated. We used a molecular population genetics approach to test evolutionary hypotheses for the two intact opsin genes of the fully nocturnal aye-aye (Daubentonia madagascariensis), a highly unusual and endangered Madagascar primate. No evidence of gene degradation in either opsin gene was observed for any of 8 aye-aye individuals examined. Furthermore, levels of nucleotide diversity for opsin gene functional sites were lower than those for 15 neutrally evolving intergenic regions (>25 kb in total), which is consistent with a history of purifying selection on aye-aye opsin genes. The most likely explanation for these findings is that dichromacy is advantageous for aye-ayes despite their nocturnal activity pattern. We speculate that dichromatic nocturnal primates may be able to perceive color while foraging under moonlight conditions, and suggest that behavioral and ecological comparisons among dichromatic and monochromatic nocturnal primates will help to elucidate the specific activities for which color vision perception is advantageous.Molecular Biology and Evolution 10/2007; 24(9):1963-70. · 5.55 Impact Factor -
Article: The evolutionary history of human and chimpanzee Y-chromosome gene loss.
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ABSTRACT: Recent studies have suggested that gene gain and loss may contribute significantly to the divergence between humans and chimpanzees. Initial comparisons of the human and chimpanzee Y-chromosomes indicate that chimpanzees have a disproportionate loss of Y-chromosome genes, which may have implications for the adaptive evolution of sex-specific as well as reproductive traits, especially because one of the genes lost in chimpanzees is critically involved in spermatogenesis in humans. Here we have characterized Y-chromosome sequences in gorilla, bonobo, and several chimpanzee subspecies for 7 chimpanzee gene-disruptive mutations. Our analyses show that 6 of these gene-disruptive mutations predate chimpanzee-bonobo divergence at approximately 1.8 MYA, which indicates significant Y-chromosome change in the chimpanzee lineage relatively early in the evolutionary divergence of humans and chimpanzees.Molecular Biology and Evolution 04/2007; 24(3):853-9. · 5.55 Impact Factor -
Article: Focusing on comparative ape population genetics in the post-genomic age.
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ABSTRACT: The initial human and chimpanzee genome sequences have been published, and additional primate genomes, including those of gorilla and orang-utan, are in progress. With these new resources, we can now address what makes our species unique, by focusing on the underlying genetic differences associated with phenotypes. Comparative primate population genomics, including studies of structural changes, mobile elements, gene expression and functional analyses, will shed light on how natural selection and population demography are involved in the processes that lead to differences among great apes. Historically, this research has focused on the human perspective; however, we will learn much about ourselves with a focus on genomic diversity in hominoids as a group.Current Opinion in Genetics & Development 01/2007; 16(6):586-91. · 8.09 Impact Factor -
Article: Contrasting histories of G6PD molecular evolution and malarial resistance in humans and chimpanzees.
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ABSTRACT: Although mutations in the glucose-6-phosphate dehydrogenase (G6PD) gene result in several blood-related diseases in humans, they also confer resistance to malarial infection. This association between G6PD and malaria was supported by population genetic analyses of the G6PD locus, which indicated that these mutations may have recently risen in frequency in certain geographic regions as a result of positive selection. Here we characterize nucleotide sequence variation in a 5.2-kb region of the G6PD locus in a population sample of 56 chimpanzees, as well as among 7 other nonhuman primates, to compare with that in humans in determining whether other primates that are impacted by malaria also exhibit patterns of G6PD polymorphism or divergence consistent with positive selection. We find that chimpanzees have several amino acid variants but that the overall pattern at G6PD in chimpanzees, as well as in Old and New World primates in general, can be explained by recent purifying selection as well as strong functional constraint dating back to at least 30-40 MYA. These comparative analyses suggest that the recent signature of positive selection at G6PD in humans is unique.Molecular Biology and Evolution 09/2006; 23(8):1592-601. · 5.55 Impact Factor -
Article: "Ground truth" for selection on CCR5-Delta32.
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ABSTRACT: A much-celebrated story of positive selection in the human genome is the 32-bp deletion in the chemokine receptor CCR5, a variant that confers resistance to AIDS. This variant was postulated to be a relatively recent response to plague or smallpox. New research shows that the frequency of CCR5-Delta32 in Bronze Age samples is similar to that seen today, pushing the observed age of the allele back to at least 3000 and possibly 5000 years ago. Interestingly, the extent of heterozygosity, differentiation across populations and linkage disequilibrium in the CCR5 region is not dissimilar to other human genomic regions, challenging claims of recent positive selection.Trends in Genetics 07/2006; 22(6):293-6. · 10.06 Impact Factor -
Article: Molecular evolution of the primate developmental genes MSX1 and PAX9.
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ABSTRACT: In primates, the craniofacial skeleton and the dentition are marked by high levels of interspecific variation. Despite this, there are few comparative species studies conducted at the molecular level to investigate this functional diversity. We have determined nucleotide sequences of MSX1 and PAX9, two developmental genes, in a sample of 27 diverse primate species in order to identify coding or regulatory variation that may be associated with phenotypic diversity. Our analyses have identified four highly conserved noncoding sequences, including one that is conserved across primates and with dogs but not with mice. Although we find that substitution rates vary significantly across MSX1 exons, comparisons of nonsynonymous and synonymous substitution rates (dN/dS) suggest that, as a whole, MSX1 and PAX9 amino acid sequences have been under functional constraint throughout primate evolution. Compared to all other primates in our sample, our analysis of exon 1 in MSX1 finds an unusual pattern of amino acid substitution for Tarsius syrichta, a member of a lineage (tarsiers) that has many unique features among primates. For example, tarsiers are the only extant primates without deciduous incisors, and MSX1 is expressed exclusively in the incisor regions during the earliest stages of dental development. Our overall results provide insight into the utility of comparative species analyses of highly conserved developmental genes and their roles in the evolution of complex phenotypes.Molecular Biology and Evolution 04/2006; 23(3):644-54. · 5.55 Impact Factor -
Article: Comparative analyses reveal a complex history of molecular evolution for human MYH16.
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ABSTRACT: We describe the pattern of molecular evolution at a sarcomeric myosin gene, MYH16, using more than 30,000 bp of exon and intron sequence data from the chimpanzee and human genome sequencing projects to evaluate the timing and consequences of a human lineage-specific frameshift deletion. We estimate the age of the deletion at approximately 5.3 MYA. This estimate is consistent with the time of human and chimpanzee divergence and is significantly older than the first appearance of the genus Homo in the fossil record. We also find conflicting estimates of nonsynonymous fixation rates (d(N)) across different regions of this gene, revealing a complex pattern inconsistent with a simple model of pseudogene evolution for human MYH16.Molecular Biology and Evolution 04/2005; 22(3):379-82. · 5.55 Impact Factor -
Article: The citation lines of the articles in Molecular Biology and Evolution 22 (3) should have appeared as follows: Comparative Analyses Reveal a Complex History of Molecular Evolution for Human MYH16
Mol. Biol. Evol. 01/2005; 22(3):379-382. -
Article: Signatures of selection and gene conversion associated with human color vision variation.
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ABSTRACT: Trichromatic color vision in humans results from the combination of red, green, and blue photopigment opsins. Although color vision genes have been the targets of active molecular and psychophysical research on color vision abnormalities, little is known about patterns of normal genetic variation in these genes among global human populations. The current study presents nucleotide sequence analyses and tests of neutrality for a 5.5-kb region of the X-linked long-wave "red" opsin gene (OPN1LW) in 236 individuals from ethnically diverse human populations. Our analysis of the recombination landscape across OPN1LW reveals an unusual haplotype structure associated with amino acid replacement variation in exon 3 that is consistent with gene conversion. Compared with the absence of OPN1LW amino acid replacement fixation since divergence from chimpanzee, the human population exhibits a significant excess of high-frequency OPN1LW replacements. Our results suggest that subtle changes in L-cone opsin wavelength absorption may have been adaptive during human evolution.The American Journal of Human Genetics 10/2004; 75(3):363-75. · 10.60 Impact Factor -
Article: Role of evolutionary history on haplotype block structure in the human genome: implications for disease mapping.
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ABSTRACT: With the completion of the first draft of the human genome sequencing project, a new challenge is to characterize patterns of linkage disequilibrium and haplotype structure across genomic regions to identify mutations associated with complex disease. Recent work shows considerable linkage disequilibrium heterogeneity, where genomic regions of extended haplotype blocks are punctuated by recombination hotspots. In this review we explore some of the current approaches to defining and characterizing 'hapblocks', mechanisms by which hapblocks may be generated, and the implications this block-like structure may have for successfully mapping mutations associated with complex disease.Current Opinion in Genetics & Development 01/2004; 13(6):569-75. · 8.09 Impact Factor -
Article: Patterns of human genetic diversity: implications for human evolutionary history and disease.
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ABSTRACT: Since the completion of the human genome sequencing project, the discovery and characterization of human genetic variation is a principal focus for future research. Comparative studies across ethnically diverse human populations and across human and nonhuman primate species is important for reconstructing human evolutionary history and for understanding the genetic basis of human disease. In this review, we summarize data on patterns of human genetic diversity and the evolutionary forces (mutation, genetic drift, migration, and selection) that have shaped these patterns of variation across both human populations and the genome. African population samples typically have higher levels of genetic diversity, a complex population substructure, and low levels of linkage disequilibrium (LD) relative to non-African populations. We discuss these differences and their implications for mapping disease genes and for understanding how population and genomic diversity have been important in the evolution, differentiation, and adaptation of humans.Annual Review of Genomics and Human Genetics 02/2003; 4:293-340. · 14.83 Impact Factor -
Article: Evidence for balancing selection from nucleotide sequence analyses of human G6PD.
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ABSTRACT: Glucose-6-phosphate dehydrogenase (G6PD) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of the best examples of selection in the human genome. In the present study, we characterize the nucleotide diversity across a 5.2-kb region of G6PD in a sample of 160 Africans and 56 non-Africans, to determine how selection has shaped patterns of DNA variation at this gene. Our global sample of enzymatically normal B alleles and A, A-, and Med alleles with reduced enzyme activities reveals many previously uncharacterized silent-site polymorphisms. In comparison with the absence of amino acid divergence between human and chimpanzee G6PD sequences, we find that the number of G6PD amino acid polymorphisms in human populations is significantly high. Unlike many other G6PD-activity alleles with reduced activity, we find that the age of the A variant, which is common in Africa, may not be consistent with the recent emergence of severe malaria and therefore may have originally had a historically different adaptive function. Overall, our observations strongly support previous genotype-phenotype association studies that proposed that balancing selection maintains G6PD deficiencies within human populations. The present study demonstrates that nucleotide sequence analyses can reveal signatures of both historical and recent selection in the genome and may elucidate the impact that infectious disease has had during human evolution.The American Journal of Human Genetics 12/2002; 71(5):1112-28. · 10.60 Impact Factor -
Article: Molecular characterization of G6PD deficiency in Cyprus.
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ABSTRACT: In the present study, we determined the frequency of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Cyprus using two different procedures in two separate adult population groups: a semiquantitative fluorescence test on blood spotted on filter paper and a quantitative spectrophotometric test on liquid blood. The frequency of G6PD deficiency among healthy adult males was found to be 5.1% using the semiquantitative procedure and 6.4% using the quantitative procedure. Neither method was able to detect all the expected female heterozygotes (5.3% and 47.1% of the expected number, respectively). A total of 21 male hemizygotes, 1 female homozygote and 9 female heterozygotes that tested positive for G6PD deficiency were studied at the molecular level. All 32 chromosomes were genotyped and five different mutations were identified. The Mediterranean mutation in exon 6 (563C-->T) (Ser188Phe) was found to be the most common variant in the Cypriot population, accounting for 52.6% of the deficient alleles. In the remaining chromosomes, four different mutations were identified: three known mutations, Kaiping 1388G-->A (Arg463His), Chatham 1003G-->A (Ala335Thr) and Acrokorinthos 463C-->G (His155Asp), and one previously undescribed mutation in exon 3, 148C-->T (Pro50Ser), which we called G6PD Kambos. We conclude that the frequency of G6PD deficiency in Cypriot males is 6.4%, and that this deficiency is the result of several different mutations. Although all the individuals carrying the Mediterranean variant can be detected using a semiquantitative screening method, a quantitative enzyme measurement is required to detect the G6PD variants with less severe enzyme deficiencies, while the most appropriate method for heterozygote detection is DNA analysis.Blood Cells Molecules and Diseases 33(1):25-30. · 2.35 Impact Factor -
Article: ‘Ground truth’ for selection on CCR5-Δ32
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ABSTRACT: A much-celebrated story of positive selection in the human genome is the 32-bp deletion in the chemokine receptor CCR5, a variant that confers resistance to AIDS. This variant was postulated to be a relatively recent response to plague or smallpox. New research shows that the frequency of CCR5-Δ32 in Bronze Age samples is similar to that seen today, pushing the observed age of the allele back to at least 3000 and possibly 5000 years ago. Interestingly, the extent of heterozygosity, differentiation across populations and linkage disequilibrium in the CCR5 region is not dissimilar to other human genomic regions, challenging claims of recent positive selection.Trends in Genetics.
Top co-authors
Top Journals
Institutions
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2006–2012
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Arizona State University
- • Department of Psychology
- • Centre for Evolutionary Functional Genomics
- • School of Human Evolution and Social Change
- • School of Life Sciences
Mesa, AZ, USA
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2002–2004
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University of Maryland, College Park
- Department of Biology
College Park, MD, USA
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