Markers and methods for reconstructing modern human history.
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Algorithms↗
Biomedical subjects
M D Shriver
Publications and source records attributed to M D Shriver.
Ethnic variation as a key to the biology of human disease.
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Acetaldehyde↗
The high mobility group I-C gene (HMGI-C): polymorphism and genetic localization.
We have identified a highly informative dinucleotide repeat in the 5'-flanking region of the human high mobility group I-C (HMGI-C) gene. This polymorphism consists of 18-37 copies of a (CT) repeat with an observed heterozygosity of 82-83% in African Americans and Caucasians. Linkage analysis in CEPH pedigrees localized the HMGI-C gene to chromosome region 12q13-15 with no recombination observed between HMCI-C and markers D12S102 and D12S8.
Black or African American↗
Enhanced performance feedback to strengthen biofeedback treatment outcome with childhood migraine.
Recent research has indicated that both the magnitude and frequency of performance feedback may be important variables in the biofeedback treatment of headaches. The purpose of this research was to determine whether the qualitative and/or quantitative enhancement of performance feedback could improve the efficacy of thermal biofeedback as a treatment for childhood migraine. In a time-lagged control design, six children with migraine headaches were exposed to thermal biofeedback training and then provided performance feedback reflecting moderate and high success, and, if needed, increased feedback frequency. In four of six subjects, clinically significant reductions in headache activity corresponded directly with the addition of feedback suggesting marked improvement in handwarming relative to peers, even when no improvement in handwarming had actually occurred. In two other subjects, clinically significant changes in headache activity were reported only after performance feedback frequency was increased. The results support the importance of attending to both qualitative and quantitative parameters of feedback as well as skill acquisition during thermal biofeedback treatment of children with migraine.
Adolescent↗
Microsatellite DNA variation and the evolution, domestication and phylogeography of taurine and zebu cattle (Bos taurus and Bos indicus).
Genetic variation at 20 microsatellite loci was surveyed to determine the evolutionary relationships and molecular biogeography of 20 different cattle populations from Africa, Europe and Asia. Phylogenetic reconstruction and multivariate analysis highlighted a marked distinction between humpless (taurine) and humped (zebu) cattle, providing strong support for a separate origin for domesticated zebu cattle. A molecular clock calculation using bison (Bison sp.) as an outgroup gave an estimated divergence time between the two subspecies of 610,000-850,000 years. Substantial differences in the distribution of alleles at 10 of these loci were observed between zebu and taurine cattle. These markers subsequently proved very useful for investigations of gene flow and admixture in African populations. When these data were considered in conjunction with previous mitochondrial and Y chromosomal studies, a distinctive male-mediated pattern of zebu genetic introgression was revealed. The introgression of zebu-specific alleles in African cattle afforded a high resolution perspective on the hybrid nature of African cattle populations and also suggested that certain West African populations of valuable disease-tolerant taurine cattle are under threat of genetic absorption by migrating zebu herds.
Africa, Western↗
Microsatellite data support an early population expansion in Africa.
We have developed a method for the analysis of microsatellite data that is useful in the elucidation of the demographic history of populations. This method, the PK distribution method of pairwise comparisons, is analogous to the mismatch distribution of sequence comparisons developed for the analysis of mitochondrial sequence data by Rodgers and Harpending and is defined as the distribution of the number of repeat unit differences between alleles when each allele in a sample is compared with every other allele in the sample. Using computer simulations of microsatellite loci, we show that the shape of the distribution of PK changes in a distinctive manner as a function either of time since population expansion or effective population size. Increases in both of these affect the PK distribution in a similar fashion leading to a change from a steep distribution with a Po peak to one with a nonzero peak. Analysis of three data sets from surveys of microsatellite loci in ethnographically defined populations reveals that most (9/12) of the African populations analyzed, but none of the 30 non-African populations showed PK distributions with nonzero peaks. These PK distributions indicate either an earlier expansion or a larger effective population size for African populations. This observation is consistent with the hypothesized African origin of modern human.
Africa↗
Defining child noncompliance: an examination of temporal parameters.
This study examined compliance parameters for 53 clinic-referred and nonreferred children, ages 2 to 10 years. Although there were significant differences between the referred and nonreferred samples for percentage compliance, there were no significant differences between the referred and nonreferred samples in terms of initiation or completion latencies. The average initiation latency was 5.92 s, whereas 98% of the sample initiated compliance within 14 s. Younger children did take longer to complete tasks. Results suggest that the use of short latencies in defining noncompliance may represent overly conservative criteria.
Behavior Therapy↗
Ethnic-affiliation estimation by use of population-specific DNA markers.
During the past 10 years, DNA analysis has revolutionized the determination of identity in a forensic context. Statements about the biological identity of two human DNA samples now can be made with complete confidence. Although DNA markers are very powerful for distinguishing among individuals, most offer little power to distinguish ethnicity or to support any statement about the physical characteristics of an individual. Through a search of the literature and of unpublished data on allele frequencies we have identified a panel of population-specific genetic markers that enable robust ethnic-affiliation estimation for major U.S. resident populations. In this report, we identify these loci and present their levels of allele-frequency differential between ethnically defined samples, and we demonstrate, using log-likelihood analysis, that this panel of markers provides significant statistical power for ethnic-affiliation estimation. In addition to their use in forensic ethnic-affiliation estimation, population-specific genetic markers are very useful in both population- and individual-level admixture estimation and in mapping genes by use of the linkage disequilibrium created when populations hybridize.
Alleles↗
Dispersion of human Y chromosome haplotypes based on five microsatellites in global populations.
We have analyzed five microsatellite loci from the nonrecombining portion of the human Y chromosome in 15 diverse human populations to evaluate their usefulness in the reconstruction of human evolution and early male migrations. The results show that, in general, most populations have the same set of the most frequent alleles at these loci. Hypothetical ancestral haplotypes, reconstructed on the basis of these alleles and their close derivatives, are shared by multiple populations across racial and geographical boundaries. A network of the observed haplotypes is characterized by a lack of clustering of geographically proximal populations. In spite of this, few distinct clusters of closely related populations emerged in the network, which are associated with population-specific alleles. A tree based on allele frequencies also shows similar results. Lack of haplotypic structure associated with the presumed ancestral haplotypes consisting of individuals from almost all populations indicate a recent common ancestry and/or extensive male migration during human evolutionary history. The convergent nature of microsatellite mutation confounds population relationships. Optimum resolution of Y chromosome evolution will require the use of additional microsatellite loci and diallelic genetic markers with lower mutation rates.
Alleles↗
Distribution and evolution of CTG repeats at the myotonin protein kinase gene in human populations.
We have analyzed the CTG repeat length and the neighboring Alu insertion/deletion (+/-) polymorphism in DNA samples from 16 ethnically and geographically diverse human populations to understand the evolutionary dynamics of the myotonic dystrophy-associated CTG repeat. Our results show that the CTG repeat length is variable in human populations. Although the (CTG)5 repeat is the most common allele in the majority of populations, this allele is absent among Costa Ricans and New Guinea highlanders. We have detected a (CTG)4 repeat allele, the smallest CTG known allele, in an American Samoan individual. (CTG) > or = 19 alleles are the most frequent in Europeans followed by the populations of Asian origin and are absent or rare in Africans. To understand the evolution of CTG repeats, we have used haplotype data from the CTG repeat and Alu(+/-) locus. Our results are consistent with previous studies, which show that among individuals of Caucasian and Japanese origin, the association of the Alu(+) allele with CTG repeats of 5 and > or = 19 is complete, whereas the Alu(-) allele is associated with (CTG)11-16 repeats. However, these associations are not exclusive in non-Caucasian populations. Most significantly, we have detected the (CTG)5 repeat allele on an Alu(-) background in several populations including Native Africans. As no (CTG)5 repeat allele on an Alu(-) background was observed thus far, it was proposed that the Alu(-) allele arose on a (CTG)11-13 background. Our data now suggest that the most parsimonious evolutionary model is (1) (CTG)5-Alu(+) is the ancestral haplotype; (2) (CTG)5-Alu(-) arose from a (CTG)5-Alu(+) chromosome later in evolution; and (3) expansion of CTG alleles occurred from (CTG)5 alleles on both Alu(+) and Alu(-) backgrounds.
Biological Evolution↗
Segregation distortion of the CTG repeats at the myotonic dystrophy locus.
Myotonic dystrophy (DM), an autosomal dominant neuromuscular disease, is caused by a CTG-repeat expansion, with affected individuals having > or = 50 repeats of this trinucleotide, at the DMPK locus of human chromosome 19q13.3. Severely affected individuals die early in life; the milder form of this disease reduces reproductive ability. Alleles in the normal range of CTG repeats are not as unstable as the (CTG)(> or = 50) alleles. In the DM families, anticipation and parental bias of allelic expansions have been noted. However, data on mechanism of maintenance of DM in populations are conflicting. We present a maximum-likelihood model for examining segregation distortion of CTG-repeat alleles in normal families. Analyzing 726 meiotic events in 95 nuclear families from the CEPH panel pedigrees, we find evidence of preferential transmission of larger alleles (of size < or = 29 repeats) from females (the probability of transmission of larger alleles is .565 +/- 0.03, different from .5 at P approximately equal .028). There is no evidence of segregation distortion during male meiosis. We propose a hypothesis that preferential transmission of larger CTG-repeat alleles during female meiosis can compensate for mutational contraction of repeats within the normal allelic size range, and reduced viability and fertility of affected individuals. Thus, the pool of premutant alleles at the DM locus can be maintained in populations, which can subsequently mutate to the full mutation status to give rise to DM.
Alleles↗
Intra- and inter-population diversity at short tandem repeat loci in diverse populations of the world.
To study the level of intra- and inter-population variation at hypervariable DNA loci, we have characterized 15 human populations of diverse ethnic and geographic origins at six short tandem repeat loci by using the polymerase chain reaction. Even though the spectrum of allelic variation is quite broad and there are substantial differences in allele frequency distributions among populations, in general, population within a major racial group show a greater degree of similarity. This observation is reflected in the analysis of gene diversity. When the total diversity is apportioned, the maximum variation becomes attributable to inter-individual differences within a population; of the variation that is attributed to differences between populations within a racial group and differences between racial groups, namely, African, Caucasian, and Mongoloid, than the American Indians and the Pacific Islanders. As expected, a reciprocal relationship between gene diversity and FST levels is observed. Higher values of FST in the American Indian and the Pacific Islanders may reflect smaller population size and a higher level of isolation. An analysis of genetic distance encompassing the populations belonging to the three major racial groups recognizes three distinct clusters - all the populations of African affiliation cluster together, as do the Caucasian affiliated and the Mongoloid groups, in two distinct clusters. Interestingly, three broadly classified cosmopolitan US populations, namely, US White, US Black and US Asian, cluster with their ancestrally related populations. This study dispels some of the concerns regarding the applicability of DNA typing data for forensic use.
Alleles↗
Nucleotide sequence analysis of the apolipoprotein B 3' VNTR.
Variable number of tandem repeat (VNTR) loci typically exhibit high rates of germline mutations that alter allele length and thus are ideal models for examining processes governing repeat sequence instability. We have characterized by nucleotide sequencing the internal structure of the apolipoprotein B (Apo B) 3' VNTR in a sample of same- and different-sized alleles previously associated with flanking marker haplotypes. Significant linkage disequilibrium between flanking polymorphisms and minisatellite alleles excludes unequal recombination as the predominant mechanism of mutation at the Apo B VNTR and is consistent with intra-allelic mutational processes such as replication slippage and/or unequal sister chromatid exchange. Diversity among different length alleles was distinctly polar and was usually attributable to changes in copy number at one particular repeat sequence. Analysis of predicted secondary structures for the dimeric repeats demonstrated a relationship between variability and the potential to form self-complementary intermediates. Preferential instability of the variable repeat: (i) was a function of its location within the tandem array; (ii) was not solely dependent on copy number; and (iii) may be related to the base composition of the VNTR and the degree of self-complementarity between the dimeric repeat sequences. The data suggest that polarized variability may be independent of the mutational process(es) generating length variation at minisatellite loci and suggest a possible alternative mechanism of mutation that involves the formation of secondary structures.
Alleles↗
A novel measure of genetic distance for highly polymorphic tandem repeat loci.
Genetic distance measures are indicators of relatedness among populations or species and are useful for reconstructing the historic and phylogenetic relationships among such groups. Classical measures of genetic distance were developed to analyze biochemical and serological polymorphisms, systems which generally show limited variability. However, these traditional measures of genetic distance are inadequate for the analysis of certain classes of variable number tandem repeat (VNTR) loci, which have a larger number of alleles and higher levels of heterozygosity than traditional genetic markers. At the higher levels of heterozygosity observed at these loci, the standard measures of genetic distance are nonlinear and do not account for the mutational mechanisms of hypervariable loci. We have developed a measure of genetic distance, DSW, which is appropriate for the analysis of highly polymorphic DNA loci. Using computer simulations of diverging populations, we show that DSW conforms to linearity and that the variance is similar in magnitude to traditional measures of genetic distance. Comparisons of phylogenetic trees derived from the simulated divergence of human racial groups demonstrate that the branch lengths of trees prepared using DSW are more similar to the model tree than those generated using other measures. Finally, we demonstrate the applicability of DSW to evolutionary analysis by reconstructing the relationships among eight human populations using 14 microsatellite and STR loci. The phylogenetic trees generated using DSW are different from trees constructed with traditional measures and better reflect the well-documented ancient divergence of African and non-African populations.
Animals↗
Behavioral management of children's seizure activity. Intervention guidelines for primary-care providers.
We present behavioral treatment guidelines, based on empirically established behavioral interventions, for pediatric paroxysmal disorders. The guidelines include affirming the disability and normalizing the role of the environment; teaching the child anticonvulsant coping behaviors; giving caregivers guidelines to encourage independent functioning; and involving teachers and other supervising adults in treatment. The guidelines were developed for economic feasibility, time efficiency, and easy execution in any primary-care clinic. A patient report demonstrates significant reduction in drug-refractory seizures in an 11-year-old girl by implementing the guidelines. Discussion is provided on effective implementation of the behavioral guidelines in the primary-care clinic.
Adaptation, Psychological↗
Normal CAG repeat variation at the DRPLA locus in world populations.
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Alleles↗
Population genetics of dinucleotide (dC-dA)n.(dG-dT)n polymorphisms in world populations.
We have characterized eight dinucleotide (dC-dA)n.(dG-dT)n repeat loci located on human chromosome 13q in eight human populations and in a sample of chimpanzees. Even though there is substantial variation in allele frequencies at each locus, at a given locus the most frequent alleles are shared by all human populations. The level of heterozygosity is reduced in isolated or small populations, such as the Pehuenche Indians of Chile, the Dogrib of Canada, and the New Guinea highlanders. On the other hand, larger average heterozygosities are observed in large and cosmopolitan populations, such as the Sokoto population from Nigeria and German Caucasians. Conformity with Hardy-Weinberg equilibrium is generally observed at these loci, unless (a) a population is isolated or small or (b) the repeat motif of the locus is not perfect (e.g., D13S197). Multilocus genotype probabilities at these microsatellite loci do not show departure from the independence rule, unless the loci are closely linked. The allele size distributions at these (CA)n loci do not follow a strict single-step stepwise-mutation model. However, this features does not compromise the ability to detect population affinities, when these loci are used simultaneously. The microsatellite loci examined here are present and, with the exception of the locus D13S197, are polymorphic in the chimpanzees, showing an overlapping distribution of allele sizes with those observed in human populations.
Alleles↗
Conservation of human chromosome 13 polymorphic microsatellite (CA)n repeats in chimpanzees.
Tandemly repeated (dC-dA)n.(dG-dT)n sequences occur abundantly and are found in most eukaryotic genomes. To investigate the level of conservation of these repeat sequences in nonhuman primates, we have analyzed seven human chromosome 13 dinucleotide (CA)n repeat loci in chimpanzees by DNA amplification using primers designed for analysis of human loci. Comparable levels of polymorphism at these loci in the two species, revealed by the number of alleles, heterozygosity, and allele sizes, suggest that the (CA)n repeat arrays and their genomic locations are highly conserved. Even though the proportion of shared alleles between the two species varies enormously and the modal alleles are not the same, allelic lengths at each locus in the chimpanzees are detected within the bounds of the allele size range observed in humans. A similar observation has been noted in a limited number of gorillas and orangutans. Using a new measure of genetic distance that takes into account the size of alleles, we have compared the genetic distance between humans and chimpanzees. The genetic distance between these two species was found to be ninefold smaller than expected assuming there is no selection or mutational bias toward retention of (CA)n repeat arrays. These findings suggest a functional significance for these microsatellite loci.
Alleles↗