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PubMed2005

Parent-of-origin, imprinting, mitochondrial, and X-linked effects in traits related to alcohol dependence: presentation Group 18 of Genetic Analysis Workshop 14.

The participants of Presentation Group 18 of Genetic Analysis Workshop 14 analyzed the Collaborative Study on the Genetics of Alcoholism data set to investigate sex-specific effects for phenotypes related to alcohol dependence. In particular, the participants looked at imprinting (which is also known as parent-of-origin effect), differences between recombination fractions for the two sexes, and mitochondrial and X-chromosomal effects. Five of the seven groups employed newly developed or existing methods that take imprinting into account when testing for linkage, or test for imprinting itself. Single-marker and multipoint analyses were performed for microsatellite as well as single-nucleotide polymorphism markers, and several groups used a sex-specific genetic map in addition to a sex-averaged map. Evidence for paternal imprinting (i.e., maternal expression) was consistently obtained by at least two groups at genetic regions on chromosomes 10, 12, and 21 that possibly harbor genes responsible for alcoholism. Evidence for maternal imprinting (which is equivalent to paternal expression) was consistently found at a locus on chromosome 11. Two groups applied extensions of variance components analysis that model a mitochondrial or X-chromosomal effect to latent class variables and electrophysiological traits employed in the diagnosis of alcoholism. The analysis, without using genetic markers, revealed mitochondrial or X-chromosomal effects for several of these traits. Accounting for sex-specific environmental variances appeared to be crucial for the identification of an X-chromosomal factor. In linkage analysis using marker data, modeling a mitochondrial variance component increased the linkage signals obtained for autosomal loci.

Alcoholism↗
PubMed1994

Statistical analysis of length of productive life for dairy cows of the Normande breed.

The length of productive life of 103,214 Normande cows milked from 1979 to 1989 in purebred herds was analyzed using a mixed Weibull model: their probability of being culled, or hazard function, was supposed to be the product of a baseline Weibull hazard function and explanatory variables that were log-linear and time-dependent. Fixed effects that may have an impact on culling rate were successively added to the model. Two random effects, a herd-year and a sire effect, were also included. The dispersion parameter of the log-gamma prior distributions assumed for these effects was estimated maximizing a marginal posterior density obtained after algebraic integration of the corresponding random effect. The other effects and the Weibull parameter could not be integrated out easily. The probability of being culled was not changed by age at first calving but increased with stage of lactation. It also increased for low producing cows and for herds of decreasing size, especially during the 3 mo preceding the end of the period on which yearly milk production is calculated for the European Community quota system. This last phenomenon seems to be crucial for proper statistical and genetic analysis of length of productive life. The estimated variances of the herd-year and sire effects indicated a large influence of these effects on culling rate. Under certain assumptions, the standard deviation of sire effects can be assessed at > .5 expected complete lactations. This value is not reduced by consideration of differences in milk production of the cows.

Aging↗
PubMed2002

Nuclear and mitochondrial genetic variation in the Yanomamö: a test case for ancient DNA studies of prehistoric populations.

Ancient DNA provides a potentially revolutionary way to study biological relationships in prehistoric populations, but genetic patterns are complex and require careful interpretation based on robust, well-tested models. In this study, nuclear and mitochondrial markers were compared in the Yanomamö, to assess how well each data set could differentiate among closely related groups. The villages selected for the study share a recent fission history and are closely related to each other, as would likely be the case among prehistoric peoples living in the same valley or region. The Yanomamö generally practice village-level endogamy, but some migration and gene flow are known to occur between villages. Nuclear and mitochondrial DNA data were compared using F-statistics and genetic distance analyses. The nuclear data performed as expected, males and females from the same village were similar, and the villages were genetically distinct, with the magnitude of genetic differences correlated with historical relationship. However, mtDNA analyses did not yield the expected results. The genetic distances between villages did not correlate with historical relationship, and the sexes were significantly different from each other in two villages. Both the Lane and Sublett and the Spence methods, used to test for archaeological residence patterns, were consistent with endogamy. Hence, ancient DNA can, in principle, provide us with a unique opportunity to study genetic structure and gene flow in archaeological populations. However, interpretations, particularly those based on single loci such as mitochondrial DNA, should be cautious because sex-specific migration and sampling issues may have dramatic effects.

Adult↗
PubMed2006

Comment on "Statistical independence of escalatory ecological trends in Phanerozoic marine invertebrates".

Madin et al. (Reports, 12 May 2006, p. 897) reported that escalation has not been an important cause of biological change throughout the history of life. However, they evaluated the escalation hypothesis with inappropriate data. First, global-scale data integrate heterogeneous signals that obscure the economic context of life. Second, diversity data cannot yield information about selection and adaptation.

Adaptation, Biological↗
PubMed2005

Contrasting patterns of Y-chromosome variation in South Siberian populations from Baikal and Altai-Sayan regions.

In order to investigate the genetic history of autochthonous South Siberian populations and to estimate the contribution of distinct patrilineages to their gene pools, we have analyzed 17 Y-chromosomal binary markers (YAP, RPS4Y(711), SRY-8299, M89, M201, M52, M170, 12f2, M9, M20, 92R7, SRY-1532, DYS199, M173, M17, Tat, and LLY22 g) in a total sample of 1,358 males from 14 ethnic groups of Siberia (Altaians-Kizhi, Teleuts, Shors, Tuvinians, Todjins, Tofalars, Sojots, Khakassians, Buryats, Evenks), Central/Eastern Asia (Mongolians and Koreans) and Eastern Europe (Kalmyks and Russians). Based on both, the distribution pattern of Y-chromosomal haplogroups and results on AMOVA analysis we observed the statistically significant genetic differentiation between the populations of Baikal and Altai-Sayan regions. We suggest that these regional differences can be best explained by different contribution of Central/Eastern Asian and Eastern European paternal lineages into gene pools of modern South Siberians. The population of the Baikal region demonstrates the prevalence of Central/Eastern Asian lineages, whereas in the populations of Altai and Sayan regions the highest paternal contribution resulted from Eastern European descent is revealed. Yet, our data on Y-chromosome STRs variation demonstrate the clear differences between the South Siberian and Eastern European R1a1-lineages with the evolutionary ages compatible with divergence time between these two regional groups.

Chromosomes, Human, Y↗
PubMed1999

Effects of misclassification on estimates of relative risk in family history studies.

Two types of misclassification that commonly occur in family-genetic studies are distinguished: 1) nondifferential misclassification, in which the probability of error as to phenotype (presence or absence of psychiatric disorder) does not depend on exposure status (being kin to a case or control proband) and 2) differential misclassification, in which it does. Nondifferential misclassification of phenotype reduces the observed relative risk towards the null value, sometimes quite dramatically. Differential misclassification can bias the observed relative risk in either direction, depending on the different values of sensitivity and specificity among relatives of cases and controls. The impact of these biases on genetic-epidemiologic studies is reviewed and discussed. In particular, the ability to detect major gene effects from the pattern of relative risks in first-, second-, and third-degree relatives can be severely compromised. Although there are some methods available to correct the effects of nondifferential misclassification, a major priority for family history studies is to minimize differential misclassification.

Bias↗
PubMed2004

Population history of native groups in pre- and postcontact Spanish Florida: aggregation, gene flow, and genetic drift on the Southeastern U.S. Atlantic coast.

Evolutionary trends and population history and structure are discussed for a series of late prehistoric and historic-period skeletal samples from the Georgia coast and interior (the Guale). Phenotypic dental measurement data were collected for nine samples from the late prehistoric (AD 1200-1400) and historic (AD 1608-1702) periods and subjected to population genetic and statistical analyses. The primary trends were for an increase in tooth size through time, and for an initial increase in dental variability in the early historic period, followed by a subsequent decline in dental variability in the late historic period. Given the increasing stress levels, evidenced by previous bioarchaeological analyses (Larsen [2001] Bioarchaeology of Spanish Florida, Gainesville: University Press of Florida), an environmental explanation for the increase in tooth size is unlikely. It is proposed that the early historic period witnessed aggregation and gene flow with extraregional populations, possibly African slaves or nonlocal Native American population groups. The late historic period may have experienced significant loss of phenotypic variability due to genetic drift. In both time periods, the evolutionary mechanism increased average tooth size, with independent variance effects.Because microevolutionary trends obscure patterns of gene flow and population ancestry, the data were detrended following Konigsberg ([1990a] Hum. Biol. 62:49-70), and submitted to standard population genetic analyses (Relethford et al. [1997] Hum. Biol. 69:443-465). Analysis of the precontact samples in isolation (Irene Mound, Irene Mortuary, and an aggregate coastal sample) indicated little genetic microdifferentiation (F(ST) = 0.008), limited extralocal gene flow, and a small distinction between interior and coastal samples. The inclusion of the historic data dramatically increased variability levels (F(ST) = 0.019). The analysis of extralocal gene flow indicates that the late mission period experienced significantly less external gene flow, which is consistent with historic models that suggest the social organization of the Guale during this time period may have been significantly altered. Genetic distances also indicate a primary division between inland and coastal precontact samples and a maintenance of biological populations along the coast. In other words, the coastal, early historic, and late historic period samples are phenotypically homogeneous, supporting the notion that the mission populations were drawn from the local population base. The late mission period sample was also, however, more closely related to the interior samples. This may suggest that the late mission period population was an aggregate sample composed of both remnant interior and coastal population groups.

Colonialism↗
PubMed2006

Is the genetic structure of human personality universal? A cross-cultural twin study from North America, Europe, and Asia.

This study examined whether universality of the 5-factor model (FFM) of personality operationalized by the Revised NEO Personality Inventory is due to genetic influences that are invariant across diverse nations. Factor analyses were conducted on matrices of phenotypic, genetic, and environmental correlations estimated in a sample of 1,209 monozygotic and 701 dizygotic twin pairs from Canada, Germany, and Japan. Five genetic and environmental factors were extracted for each sample. High congruence coefficients were observed when phenotypic, genetic, and environmental factors were compared in each sample as well as when each factor was compared across samples. These results suggest that the FFM has a solid biological basis and may represent a common heritage of the human species.

Canada↗
PubMed2004

Increasing the power and efficiency of disease-marker case-control association studies through use of allele-sharing information.

Case-control disease-marker association studies are often used in the search for variants that predispose to complex diseases. One approach to increasing the power of these studies is to enrich the case sample for individuals likely to be affected because of genetic factors. In this article, we compare three case-selection strategies that use allele-sharing information with the standard strategy that selects a single individual from each family at random. In affected sibship samples, we show that, by carefully selecting sibships and/or individuals on the basis of allele sharing, we can increase the frequency of disease-associated alleles in the case sample. When these cases are compared with unrelated controls, the difference in the frequency of the disease-associated allele is therefore also increased. We find that, by choosing the affected sib who shows the most evidence for pairwise allele sharing with the other affected sibs in families, the test statistic is increased by >20%, on average, for additive models with modest genotype relative risks. In addition, we find that the per-genotype information associated with the allele sharing-based strategies is increased compared with that associated with random selection of a sib for genotyping. Even though we select sibs on the basis of a nonparametric statistic, the additional gain for selection based on the unknown underlying mode of inheritance is minimal. We show that these properties hold even when the power to detect linkage to a region in the entire sample is negligible. This approach can be extended to more-general pedigree structures and quantitative traits.

Alleles↗
PubMedDate not supplied

Biodiversity of 52 chicken populations assessed by microsatellite typing of DNA pools.

In a project on the biodiversity of chickens funded by the European Commission (EC), eight laboratories collaborated to assess the genetic variation within and between 52 populations from a wide range of chicken types. Twenty-two di-nucleotide microsatellite markers were used to genotype DNA pools of 50 birds from each population. The polymorphism measures for the average, the least polymorphic population (inbred C line) and the most polymorphic population (Gallus gallus spadiceus) were, respectively, as follows: number of alleles per locus, per population: 3.5, 1.3 and 5.2; average gene diversity across markers: 0.47, 0.05 and 0.64; and proportion of polymorphic markers: 0.91, 0.25 and 1.0. These were in good agreement with the breeding history of the populations. For instance, unselected populations were found to be more polymorphic than selected breeds such as layers. Thus DNA pools are effective in the preliminary assessment of genetic variation of populations and markers. Mean genetic distance indicates the extent to which a given population shares its genetic diversity with that of the whole tested gene pool and is a useful criterion for conservation of diversity. The distribution of population-specific (private) alleles and the amount of genetic variation shared among populations supports the hypothesis that the red jungle fowl is the main progenitor of the domesticated chicken.

Animals↗
PubMed2003

Lith6: a new QTL for cholesterol gallstones from an intercross of CAST/Ei and DBA/2J inbred mouse strains.

A complex genetic basis determines the individual predisposition to develop cholesterol gallstones in response to environmental factors. We employed quantitative trait locus/loci (QTL) analyses of an intercross between inbred strains CAST/Ei (susceptible) and DBA/2J (resistant) to determine the subset of gallstone susceptibility (Lith) genes these strains possess. Parental and first filial generation mice of both genders and male intercross offspring were evaluated for gallstone formation after feeding a lithogenic diet. Linkage analysis was performed using a form of multiple interval mapping. One significant QTL colocalized with Lith1 [chromosome (chr) 2, 50 cM], a locus identified previously. Significantly, new QTL were detected and named Lith10 (chr 6, 4 cM), Lith6 (chr 6, 54 cM), and Lith11 (chr 8, 58 cM). Statistical and genetic analyses suggest that Lith6 comprises two QTL in close proximity. Our molecular and genetic data support the candidacy of peroxisome proliferator-activated receptor gamma (Pparg) and Slc21a1, encoding Pparg, and the basolateral bile acid transporter SLC21A1 (Slc21a1/Oatp1), respectively, as genes underlying Lith6.

Alleles↗
PubMed2001

The relationship between body condition score and reproductive performance.

The aim of this study was to investigate the relationship between measures of body condition score collected from calving until wk 26 of lactation and reproductive measures (calving interval, days to first heat, days to first service, and conception at first service). Since 1973 sires of cows at the Langhill Dairy Cattle Research Centre have been selected for either high (selection line) or average (control line) genetic merit for fat plus protein. The data included 1211 records from 534 cows calving from 1988 to 1999. At first calving, cows were randomly assigned to one of two ad libitum diets: one that was relatively high in concentrates (approximately 3000 kg/yr) and one that was relatively low in concentrates (approximately 1500 kg/yr). Selection line cows were on average thinner and lost more condition in early lactation than control line cows. Cows that lost condition, those that were thinner than average at wk 10 of lactation and those that were thinner on average over the first 10 wk, had poorer reproductive performance. This effect was greatest in the selection line. Line x diet interaction effects were not statistically significant. Genetic correlations between body condition score and reproductive measures were unfavorable and ranged from -0.04 to -0.54. The relationship between body condition score and production was strong, but, even after adjusting for yield, an unfavorable relationship still exists between body condition score and fertility. Body condition score could be used as a management and selection tool to improve reproductive performance.

Animal Husbandry↗
PubMedDate not supplied

Statistical design of toxicity assays: role of genetic structure of test animal population.

This paper considers certain statistical aspects of the problem of among-strain differences in cancer susceptibilities and how these differences may affect the design of toxicity assays. First, in order to investigate the magnitude of within-study, between-strain differences in tumor induction, the data of Innes et al. (1969) were examined. It was found that although there was a very high overall association between mouse strains with respect to the induction of hepatomas, several compounds showed evidence of strain-to-strain variability. Next, a number of long-term carcinogenicity studies with DDT were considered, and among-strain differences in cancer susceptibility for this compound were noted. Finally, it was shown that if susceptible subgroups do exist and certain simplifying assumptions are made, then in many cases tumor increases can be detected more readily by using several inbred mouse strains for study rather than a single outbread stock.

Animals↗
PubMed2003

Mitochondrial DNA variability in Bosnians and Slovenians.

Mitochondrial DNA variability in two Slavonic-speaking populations of the northwestern Balkan peninsula, Bosnians (N = 144) and Slovenians (N = 104), was studied by hypervariable segments I and II (HVS I and II) sequencing and restriction fragment-length polymorphism (RFLP) analysis of the mtDNA coding region. The majority of the mtDNA detected in Southern Slavonic populations falls into the common West Eurasian mitochondrial haplogroups (e.g., H, pre-V, J, T, U, K, I, W, and X). About 2% of the Bosnian mtDNAs encompass East Eurasian and African lineages (e.g., M and L1b, respectively). The distribution of mtDNA subclusters in Bosnians, Slovenians and the neighbouring European populations reveals that the common genetic substratum characteristic for Central and Eastern European populations (such as Germans, Poles, Russians and Finns) penetrates also South European territories as far as the Western Balkans. However, the observed differentiation between Bosnian and Slovenian mtDNAs suggests that at least two different migration waves of the Slavs may have reached the Balkans in the early Middle Ages.

Bosnia and Herzegovina↗
PubMed1989

The geneticist and the so-called "socio cultural" familial mental retardation.

Five hundred children and adolescents affected by mild mental retardation were studied together with their families with regard to a number of psycho-social, medical and genetic factors. Statistical studies were performed with these data and showed that this apparently homogeneous population could in fact be divided into three subgroups. The first and by far the largest group (66%) was constituted by a clinically normal population but in whom adverse social and cultural factors were dominant. In the second subgroup (20%) the mental retardation was much more pronounced (IQ of 50----65) and the socio-cultural and socio-economic levels were particularly low. Finally, organic causes (prematurity, dystocic, labour, etc.) seemed to constitute the principal factor explaining the retardation observed in the third subgroup (14%). The second subgroup comprising of 50 children and their families, were observed more closely; in this group 20 cases of known genetic diseases were found.

Adolescent↗
PubMed2002

Effect of low doses of 5-methyltetrahydrofolate and folic acid on plasma homocysteine in healthy subjects with or without the 677C-->T polymorphism of methylenetetrahydrofolate reductase.

BACKGROUND: The 677C-->T polymorphism of methylenetetrahydrofolate reductase can lead to increased homocysteine. Moderate increases of homocysteine can be lowered by folic acid (0.4-10 mg day-1). This study compared the effect of folic acid with 5-methyltetrahydrofolate, the active form of folate generated by this reductase, on homocysteine levels in healthy subjects and whether this is influenced by the 677C-->T polymorphism. MATERIALS AND METHODS: Either 400 micrograms day-1 of [6RS] 5-methyltetrahydrofolate or 400 micrograms day-1 of folic acid were administered orally to 10 wild-type and 10 homozygous subjects. Total homocysteine and folate were determined before and after 3 and 7 weeks of treatment, and 24 weeks after stopping treatment. RESULTS: After 3 and 7 weeks of treatment with 5-methyltetrahydrofolate, homocysteine levels fell from 11.6 +/- 1.5 to 9.0 +/- 2.3 and 8.7 +/- 1.8 (P < 0.005) in wild-type subjects and from 16.9 +/- 6.8 to 12.3 +/- 4.3 and 11.6 +/- 4.4 mumol/L, mean +/- SD (P < 0.005) in homozygous subjects, proving biological availability of 5-methyltetrahydrofolate irrespective of the 677C-->T genotype. After folic acid for 3 and 7 weeks, values fell from 12.6 +/- 3.3 to 9.2 +/- 2.9 and 9.2 +/- 2.7 (P < 0.005) and from 15.6 +/- 4.9 to 11.7 +/- 3.9 and 9.1 +/- 2.4 mumol L-1, mean +/- SD (P < 0.005) in wild-type and homozygous subjects, respectively. Six months after stopping treatment, homocysteine levels remained lower than pretreatment levels, with statistical significance, only in homozygous subjects treated with 5-methyltetrahydrofolate (12.1 +/- 2.5 vs. 16.9 +/- 6.8, P < 0.01). CONCLUSIONS: 5-methyltetrahydrofolate showed comparable efficacy in reducing homocysteine as folic acid. A prolonged effect 6 months after ceasing treatment with 5-methyltetrahydrofolate in homozygous subjects represents a further phenotypic effect of the 677TT methylenetetrahydrofolate reductase genotype.

Adult↗
PubMed2002

The linkage information content value of polymorphism genetic markers in model-free linkage analysis.

Guo and Elston [Hum Hered 1999;49:112-118] developed a linkage information content (LIC) value to measure the informativeness of a marker for identity-by-descent (IBD) sharing status of relative pairs. LIC values were derived for five types of relative pairs: full sib, half sib, grandparent-grandchild, first cousin and avuncular. In this paper, we give corrected LIC values for full sib, grandparent-grandchild, first cousin and avuncular pairs, and indicate the availability of a computer program to calculate them.

Chromosome Mapping↗
PubMed2003

Correcting for ascertainment biases when analyzing SNP data: applications to the estimation of linkage disequilibrium.

As large-scale sequencing efforts turn from single genome sequencing to polymorphism discovery, single nucleotide polymorphisms (SNPs) are becoming an increasingly important class of population genetic data. But because of the ascertainment biases introduced by many methods of SNP discovery, most SNP data cannot be analyzed using classical population genetic methods. Statistical methods must instead be developed that can explicitly take into account each method of SNP discovery. Here we review some of the current methods for analyzing SNPs and derive sampling distributions for single SNPs and pairs of SNPs for some common SNP discovery schemes. We also show that the ascertainment scheme has a large effect on the estimation of linkage disequilibrium and recombination, and describe some methods of correcting for ascertainment biases when estimating recombination rates from SNP data.

Bias↗