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Biomedical subjects

Kenneth K Kidd

Publications and source records attributed to Kenneth K Kidd.

At least 19 recordsLinked to original sources
PubMed2006

Evolutionary insights into the high worldwide prevalence of MBL2 deficiency alleles.

Human mannose-binding lectin (MBL) is a member of the collectin protein family that binds a broad range of microorganisms and activates the lectin-complement pathway of innate immunity. Common alleles of MBL2 disrupt the MBL protein or modulate the amount of protein produced, resulting in MBL deficiency. The clinical manifestations of MBL deficiency have been extensively studied but the actual role of this lectin in immunity to infection remains a matter of strong debate. MBL is commonly thought to play a key role in protective immunity, because MBL deficiency has been associated with an increase in susceptibility to infectious diseases. However, the high worldwide prevalence of multiple MBL2 deficiency or low-producing alleles suggests the converse that MBL deficiency confers protection. To explore the underlying forces accounting for the high worldwide prevalence of MBL2 deficiency alleles, we characterized genetic diversity in and around the MBL2 genomic region in 1166 chromosomes from 24 worldwide populations. Our results clearly demonstrate that the patterns of MBL2 variation are compatible with neutral evolution, as opposed to negative, positive or balanced natural selection. The high worldwide frequencies of MBL2 alleles associated with the production of little or no protein therefore result exclusively from human migration and genetic drift. The evolutionary neutrality of MBL2 strongly supports the notion that MBL2 variation does not have strong effects on population fitness, suggesting, therefore, that this lectin is largely redundant in host human defences.

Alleles↗
PubMed2006

Nonsynonymous SNPs: validation characteristics, derived allele frequency patterns, and suggestive evidence for natural selection.

We experimentally investigated more than 1,200 entries in dbSNP that would change amino-acids (nsSNPs), using various subsets of DNA samples drawn from 18 global populations (approximately 1,000 subjects in total). First, we mined the data for any SNP features that correlated with a high validation rate. Useful predictors of valid SNPs included multiple submissions to dbSNP, having a dbSNP validation statement, and being present in a low number of ESTs. Together, these features improved validation rates by almost 10-fold. Higher-abundance SNPs (e.g., T/C variants) also validated more frequently. Second, we considered derived alleles and noted a considerably (approximately 10%) increased average derived allele frequency (DAF) in Europeans vs. Africans, plus a further increase in some other populations. This was not primarily due to an SNP ascertainment bias, nor to the effects of natural selection. Instead, it can be explained as a drift-based, progressive increase in DAF that occurs over many generations and becomes exaggerated during population bottlenecks. This observation could be used as the basis for novel DAF-based tests for comparing demographic histories. Finally, we considered individual marker patterns and identified 37 SNPs with allele frequency variance or FST values consistent with the effects of population-specific natural selection. Four particularly striking clusters of these markers were apparent, and three of these coincide with genes/regions from among only several dozen such domains previously suggested by others to carry signatures of selection.

Alleles↗
PubMed2006

Effects of traditional and western environments on prevalence of type 2 diabetes in Pima Indians in Mexico and the U.S.

OBJECTIVE: Type 2 diabetes and obesity have genetic and environmental determinants. We studied the effects of different environments on these diseases in Pima Indians in Mexico and the U.S. RESEARCH DESIGN AND METHODS: Adult Pima-Indian and non-Pima populations in the Sierra Madre mountains of Mexico were examined using oral glucose tolerance tests and assessments for obesity, physical activity, and other risk factors. Results were compared with those from Pima Indians in Arizona. Both Pima populations were typed for DNA polymorphisms to establish their genetic similarity. RESULTS: The age- and sex-adjusted prevalence of type 2 diabetes in the Mexican Pima Indians (6.9%) was less than one-fifth that in the U.S. Pima Indians (38%) and similar to that of non-Pima Mexicans (2.6%). The prevalence of obesity was similar in the Mexican Pima Indians (7% in men and 20% in women) and non-Pima Mexicans (9% in men and 27% in women) but was much lower than in the U.S. Pima Indians. Levels of physical activity were much higher in both Mexican groups than in the U.S. Pima Indians. The two Pima groups share considerable genetic similarity relative to other Native Americans. CONCLUSIONS: The much lower prevalence of type 2 diabetes and obesity in the Pima Indians in Mexico than in the U.S. indicates that even in populations genetically prone to these conditions, their development is determined mostly by environmental circumstances, thereby suggesting that type 2 diabetes is largely preventable. This study provides compelling evidence that changes in lifestyle associated with Westernization play a major role in the global epidemic of type 2 diabetes.

Adult↗
PubMed2005

Developing a SNP panel for forensic identification of individuals.

Single nucleotide polymorphisms (SNPs) are likely in the near future to have a fundamental role in forensics in both human identification and description. However, considerable research is necessary to establish adequate scientific foundations for these applications. In the case of identification, because allele frequencies can vary greatly among populations, the population genetics of match probabilities is a critical issue. Some SNPs, however, show little allele frequency variation among populations while remaining highly informative. We describe here both an efficient strategy for identifying and characterizing such SNPs, and test that strategy on a broad representation of world populations. Markers with high heterozygosity and little frequency variation among African American, European American, and East Asian populations are selected for additional screening on seven populations that provide a sampling of genetic variation from the world's major geographical regions. Those with little allele frequency variation on the seven populations are then screened on a total of 40 populations ( approximately 2100 individuals) and the most promising retained. The preliminary panel of 19 SNPs, from an initial selection of 195 SNPs, gives an average match probability of <10(-7) in most of 40 populations studied and no greater than 10(-6) in the most isolated, inbred populations. Expansion of this panel to approximately 50 comparable SNPs should give match probabilities of about 10(-15) with a small global range.

DNA Fingerprinting↗
PubMed2005

Epidemiology. DNA identifications after the 9/11 World Trade Center attack.

The attack on the World Trade Center on 9/11/2001 challenged current approaches to forensic DNA typing methods. The large number of victims and the extreme thermal and physical conditions of the site necessitated special approaches to the DNA-based identification. Because of these and many additional challenges, new procedures were created or modified from routine forensic protocols. This effort facilitated the identification of 1594 of the 2749 victims. In this Policy Forum, the authors, who were were members of the World Trade Center Kinship and Data Analysis Panel, review the lessons of the attack response from the perspective of DNA forensic identification and suggest policies and procedures for future mass disasters or large-scale terrorist attacks.

DNA↗
PubMed2005

HAPLOT: a graphical comparison of haplotype blocks, tagSNP sets and SNP variation for multiple populations.

UNLABELLED: Understanding of human variation relevant to association studies can benefit from population comparison, especially comparing populations in the same geographical region. Variations in linkage disequilibrium patterns, in tagSNP sets, and in SNP heterozygosities among populations can be used to infer the evolutionary pattern. We present here a win32 system based Perl/Tk application for visual comparisons of these variations in different populations. AVAILABILITY: The application package is available at http://info.med.yale.edu/genetics/kkidd/programs.html CONTACT: sheng.gu@yale.edu.

Chromosome Mapping↗
PubMed2005

Use of autosomal loci for clustering individuals and populations of East Asian origin.

We studied the genetic relationships among East Asian populations based on allele frequency differences to clarify the relative similarities of East Asian populations with a specific focus on the relationships among the Koreans, the Japanese, and the Chinese populations known to be genetically similar. The goal is to find markers appropriate for differentiating among the specific populations. In this study, no prior data existed for Koreans and the markers were selected to differentiate Chinese and Japanese. We typed, using AB TaqMan assays, single-nucleotide polymorphisms (SNPs) at 43 highly selected mostly independent diallelic sites, on 386 individuals from eight East Asian populations (Han Chinese from San Francisco, Han Chinese from Taiwan, Hakka, Koreans, Japanese, Ami, Atayal, and Cambodians) and one Siberian population (Yakut). We inferred group membership of individuals using a model-based clustering method implemented by the STRUCTURE program and population clustering by using computer programs DISTANCE, NEIGHBOR, LSSEARCH, and DRAWTREE, respectively, calculating genetic distances among populations, calculating neighbor-joining and least-squares trees, and drawing the calculated trees. On average 52% of individuals in the three Chinese groups were assigned into one cluster, and, respectively, 78 and 69% of Koreans and Japanese into a different cluster. Koreans differentiated from the Chinese groups and clustered with the Japanese in the principal component analysis (PCA) and in the best least-squares tree. The majority of Koreans were difficult to distinguish from the Japanese. This study shows that a relatively few highly selected markers can, within limits, differentiate between closely related populations.

Asian People↗
PubMed2005

Intelligence, race, and genetics.

In this article, the authors argue that the overwhelming portion of the literature on intelligence, race, and genetics is based on folk taxonomies rather than scientific analysis. They suggest that because theorists of intelligence disagree as to what it is, any consideration of its relationships to other constructs must be tentative at best. They further argue that race is a social construction with no scientific definition. Thus, studies of the relationship between race and other constructs may serve social ends but cannot serve scientific ends. No gene has yet been conclusively linked to intelligence, so attempts to provide a compelling genetic link of race to intelligence are not feasible at this time. The authors also show that heritability, a behavior-genetic concept, is inadequate in regard to providing such a link.

Genetics, Population↗
PubMed2005

Linkage disequilibrium patterns vary substantially among populations.

A major initiative to create a global human haplotype map has recently been launched as a tool to improve the efficiency of disease gene mapping. The 'HapMap' project will study common variants in depth in four (and to a lesser degree in up to 12) populations to catalogue haplotypes that are expected to be common to all populations. A hope of the 'HapMap' project is that much of the genome occurs in regions of limited diversity such that only a few of the SNPs in each region will capture the diversity and be relevant around the world. In order to explore the implications of studying only a limited number of populations, we have analyzed linkage disequilibrium (LD) patterns of three 175-320 kb genomic regions in 16 diverse populations with an emphasis on African and European populations. Analyses of these three genomic regions provide empiric demonstration of marked differences in frequencies of the same few haplotypes, resulting in differences in the amount of LD and very different sets of haplotype frequencies. These results highlight the distinction between the statistical concept of LD and the biological reality of haplotypes and their frequencies. The significant quantitative and qualitative variation in LD among populations, even for populations within a geographic region, emphasizes the importance of studying diverse populations in the HapMap project to assure broad applicability of the results.

Asian People↗
PubMed2005

Considerable haplotype diversity within the 23kb encompassing the ADH7 gene.

BACKGROUND: Of the seven known human alcohol dehydrogenase (ADH) genes, the non-liver expressed ADH7 gene codes for the enzyme with the highest maximal activity for ethanol. Previous study from our laboratory has suggested that ADH7 has an epistatic role for protection against alcoholism based on a single ADH7 SNP. METHODS: We have now studied seven SNPs, additional populations for the SNP previously examined, and six more new SNPs, across 23 kb of ADH7 in 38 population samples originating from different geographical regions of the world. RESULTS: The overall linkage disequilibrium is moderate to strong across this region even though considerable 7-SNP haplotype diversity is observed. This uncommonly high haplotype diversity is explained by high LD within each "half," the three upstream SNPs and the four downstream SNPs, but near randomization between the "halves." This division significantly simplified the haplotype pattern: only four major haplotypes account for almost all chromosomes in all populations in each "half." CONCLUSIONS: The low linkage disequilibrium between these two "halves" suggests multiple recombination(s) have occurred in this region, specifically, within intron 7. The absence of strong LD between the functional variation in ADH1B that is strongly associated with alcoholism and any of the variation in ADH7 supports the genetic independence of ADH7 in association studies. Thus, the previously observed epistatic effect of ADH7 cannot be explained by its linkage disequilibrium with a causative factor in ADH1B.

Alcohol Dehydrogenase↗
PubMed2004

Positive selection in MAOA gene is human exclusive: determination of the putative amino acid change selected in the human lineage.

Monoamine oxidase A (MAOA) is the X-linked gene responsible for deamination and subsequent degradation of several neurotransmitters and other amines. Among other activities, the gene has been shown to play a role in locomotion, circadian rhythm, and pain sensitivity and to have a critical influence on behavior and cognition. Previous studies have reported a non-neutral evolution of the gene attributable to positive selection in the human lineage. To determine whether this selection was human-exclusive or shared with other species, we performed a population genetic analysis of the pattern of nucleotide variation in non-human species, including bonobo, chimpanzee, gorilla, and orangutan. Footprints of positive selection were absent in all analyzed species, suggesting that positive selection has been recent and unique to humans. To determine which human-unique genetic changes could have been responsible for this differential evolution, the coding region of the gene was compared between human, chimpanzee, and gorilla. Only one human exclusive non-conservative change is present in the gene: Glu151Lys. This human substitution affects protein dimerization according to a three-dimensional structural model that predicts a non-negligible functional shift. This is the only candidate position at present to have been selected to fixation in humans during an episode of positive selection. Divergence analysis among species has shown that, even under positive selection in the human lineage, the MAOA gene did not experience accelerated evolution in any of the analyzed lineages, and that tools such as K(a)/ K(s) would not have detected the selective history of the gene.

Amino Acid Sequence↗
PubMed2004

Possible epistatic role of ADH7 in the protection against alcoholism.

In recent studies of the role of the alcohol dehydrogenase genes (ADH) in alcoholism the ADH1B Arg47His polymorphism appears to affect risk via a protective effect associated with the ADH1B*47His. Here we present evidence for an additional effect from outside the Class I ADH genes, presumably from functional variation at the ADH7 gene. The protective effect is restricted to one of two haplotypes identical at ADH1B but differing at an intronic SNP at ADH7 suggesting epistasis or strong linkage disequilibrium (LD).

Alcohol Dehydrogenase↗
PubMed2004

Nuclear integrations of mitochondrial DNA in gorillas.

Great ape systematics, particularly at the species level and below, is currently under debate, due in part to the recent influx of molecular data. The phylogenies of previously published mitochondrial control region (or D-loop) DNA sequences in gorillas show deep splits within West African gorillas (Gorilla gorilla gorilla), and very high levels of nucleotide diversity in this subspecies. Here we demonstrate that several previously reported D-loop haplotypes from West African gorillas are in all likelihood nuclear integrations of mitochondrial DNA. Revised estimates of the amount and pattern of mitochondrial DNA diversity in gorillas are provided, revealing two reciprocally monophyletic and highly divergent groups of gorillas, concurrent with their geographic distribution.

Animals↗
PubMed2004

Haplotype block structures show significant variation among populations.

Recent studies suggest that haplotypes tend to have block-like structures throughout the human genome. Several methods were proposed for haplotype block partitioning and for tagging single-nucleotide polymorphism (SNP) identification. In population genetics studies, several research groups compared block structures across human populations. However, the measures used to quantify population similarity are either less than satisfactory or nonexistent. In this article, we propose several similarity measures to facilitate the comparisons of haplotype structures, namely block boundaries and tagging SNPs, across populations. With these measures, we can more objectively compare haplotype block structures and tagging SNP sets between different populations. In addition, these measures allow us to compare the results of different methods for block partition and tagging SNP identification. When we applied these measures to a real data set on chromosome 10 in 16 worldwide populations, we found that in this genome region: 1) haplotype block boundaries vary among populations, with European and some African populations showing similar boundaries but other populations showing other patterns; 2) tagging SNP sets are generally similar for populations with similar haplotype block structures but differ if the block structures differ; and 3) all but one of the block finding methods we tested yield consistent results, although variations exist regarding consistency. Our tentative results show that at least in the genome region studied, it is unlikely that a common haplotype pattern exists for all human populations: many populations, even in the same geographical region, may have different haplotype patterns.

Chromosome Mapping↗
PubMed2004

Implications of biogeography of human populations for 'race' and medicine.

In this review, we focus on the biogeographical distribution of genetic variation and address whether or not populations cluster according to the popular concept of 'race'. We show that racial classifications are inadequate descriptors of the distribution of genetic variation in our species. Although populations do cluster by broad geographic regions, which generally correspond to socially recognized races, the distribution of genetic variation is quasicontinuous in clinal patterns related to geography. The broad global pattern reflects the accumulation of genetic drift associated with a recent African origin of modern humans, followed by expansion out of Africa and across the rest of the globe. Because disease genes may be geographically restricted due to mutation, genetic drift, migration and natural selection, knowledge of individual ancestry will be important for biomedical studies. Identifiers based on race will often be insufficient.

Biological Evolution↗
PubMed2004

The evolution and population genetics of the ALDH2 locus: random genetic drift, selection, and low levels of recombination.

The catalytic deficiency of human aldehyde dehydrogenase 2 (ALDH2) is caused by a nucleotide substitution (G1510A; Glu487Lys) in exon 12 of the ALDH2 locus. This SNP, and four non-coding SNPs, including one in the promoter, span 40 kb of ALDH2; these and one downstream STRP have been tested in 37 worldwide populations. Only four major SNP-defined haplotypes account for almost all chromosomes in all populations. A fifth haplotype harbours the functional variant and is only found in East Asians. Though the SNPs showed virtually no historic recombination, LD values are quite variable because of varying haplotype frequencies, demonstrating that LD is a statistical abstraction and not a fundamental aspect of the genome, and is not a function solely of recombination. Among populations, different sets of tagging SNPs, sometimes not overlapping, can be required to identify the common haplotypes. Thus, solely because haplotype frequencies vary, there is no common minimum set of tagging SNPs globally applicable. The Fst values of the promoter region SNP and the functional SNP were about two S.D. above the mean for a reference distribution of 117 autosomal biallelic markers. These high Fst values may indicate selection has operated at these or very tightly linked sites.

Aldehyde Dehydrogenase↗
PubMed2004

Bitter receptor gene (TAS2R38), 6-n-propylthiouracil (PROP) bitterness and alcohol intake.

BACKGROUND: Phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), chemically related compounds, are probes for genetic variation in bitter taste, although PROP is safer with less sulfurous odor. Threshold for PROP distinguishes nontasters (increased threshold) from tasters (lower threshold); perceived intensity subdivides tasters into medium tasters (PROP is bitter) and supertasters (PROP is very bitter). Compared with supertasters, nontasters have fewer taste papillae on the anterior tongue (fungiform papillae) and experience less negative (e.g., bitterness) and more positive (eg, sweetness) sensations from alcohol. We determined whether the TAS2R38 gene at 7q36 predicted PROP bitterness, alcohol sensation and use. METHODS: Healthy adults (53 women, 31 men; mean age 36 years)--primarily light and moderate drinkers--reported the bitterness of five PROP concentrations (0.032-3.2 mM) and intensity of 50% ethanol on the general Labeled Magnitude Scale. PROP threshold and density of fungiform papillae were also measured. Subjects had common TAS2R38 gene haplotypes [alanine-valine-isoleucine (AVI) and proline-alanine-valine (PAV)]. RESULTS: PROP bitterness varied significantly across genotypes with repeated measures ANOVA: 26 AVI/AVI homozygotes tasted less bitterness than either 37 PAV/AVI heterozygotes or 21 PAV/PAV homozygotes. The PAV/PAV group exceeded the PAV/AVI group for bitterness only for the top PROP concentrations. The elevated bitterness was musch less than if we defined the groups using psychophysical criteria. With multiple regression analyses, greater bitterness from 3.2 mM PROP was a significant predictor of greater ethanol intensity and less alcohol intake--effects separate from age and sex. Genotype was a significant predictor of alcohol intake, but not ethanol intensity. With ANOVA, AVI/AVI homozygotes reported higher alcohol use than either PAV/AVI heterozygotes or PAV/PAV homozygotes. When age effects were minimized, PROP bitterness explained more variance in alcohol intake than did the TAS2R38 genotype. CONCLUSIONS: These results support taste genetic effects on alcohol intake. PROP bitterness serves as a marker of these effects.

Adult↗