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E Heyer

Publications and source records attributed to E Heyer.

At least 19 recordsLinked to original sources
PubMed2006

Estimating sex-specific processes in human populations: Are XY-homologous markers an effective tool?

Homologous markers on the sex-specific regions of the X- and Y-chromosomes are differentially inherited through males and females, and have similar molecular characteristics. They may therefore be useful as a complement to the comparison of mtDNA and Y-chromosomal haplotypes for estimating sex-specific processes shaping human population structure. To test this idea, we analyzed XY-homologous microsatellite diversity in 33 human populations from Africa, Asia and Europe. Interpopulation comparisons suggest that the generally discordant pattern of genetic variation observed for X- and Y-linked markers could be an outcome of sex-specific migration processes (m(females)/m(males) approximately 3) or sex-specific demographic processes (N(females)/N(males) approximately 11) or a combination of both. However, intrapopulation diversity estimated by the X/Y ratio Watterson estimator (theta(H(Y))/theta(H(X))) suggests that the scenarios required to explain the global genetic variation of XY-homologous markers are many and complex, and that the sex-specific processes (effective population size and migration rate) shaping human population structures are likely to be specific to each population under study. XY-homologous markers provide an insight into the genuine complexity of sex-specific processes, and their further exploitation in human population studies seems worthwhile.

Africa↗
PubMed2004

Vlax Roma history: what do coalescent-based methods tell us?

Three coalescent-based methods allowed us to infer some aspects of the history of three Bulgarian Gypsies populations belonging to the Vlax linguistic group: the Lom, Rudari and Kalderas. We used several kinds of genetic markers: HV1 sequences of the maternally inherited mitochondrial genome and microsatellites of the paternally inherited Y chromosome and of the biparentally inherited chromosome 8. This allowed us to infer several parameters for men and women: the splitting order of the populations and the ages of the splitting events, the growth rate in each population and the migration rates between populations. Altogether, they enabled us to infer a demographic scenario that could explain the genetic diversity of Vlax Roma: recent splits occurring after the arrival in Europe, asymmetric migration flows especially for males and unequal growth rates. This represents a considerable contribution to the Vlax Roma history in comparison with the inferences from classical population genetics.

Female↗
PubMed2001

Phylogenetic and familial estimates of mitochondrial substitution rates: study of control region mutations in deep-rooting pedigrees.

We studied mutations in the mtDNA control region (CR) using deep-rooting French-Canadian pedigrees. In 508 maternal transmissions, we observed four substitutions (0.0079 per generation per 673 bp, 95% CI 0.0023-0.186). Combined with other familial studies, our results add up to 18 substitutions in 1,729 transmissions (0.0104), confirming earlier findings of much greater mutation rates in families than those based on phylogenetic comparisons. Only 12 of these mutations occurred at independent sites, whereas three positions mutated twice each, suggesting that pedigree studies preferentially reveal a fraction of highly mutable sites. Fitting the data through use of a nonuniform rate model predicts the presence of 40 (95% CI 27-54) such fast sites in the whole CR, characterized by the mutation rate of 274 per site per million generations (95% CI 138-410). The corresponding values for hypervariable regions I (HVI; 1,729 transmissions) and II (HVII; 1,956 transmissions), are 19 and 22 fast sites, with rates of 224 and 274, respectively. Because of the high probability of recurrent mutations, such sites are expected to be of no or little informativity for the evaluation of mutational distances at the phylogenetic time scale. The analysis of substitution density in the alignment of 973 HVI and 650 HVII unrelated European sequences reveals that the bulk of the sites mutate at relatively moderate and slow rates. Assuming a star-like phylogeny and an average time depth of 250 generations, we estimate the rates for HVI and HVII at 23 and 24 for the moderate sites and 1.3 and 1.0 for the slow sites. The fast, moderate, and slow sites, at the ratio of 1:2:13, respectively, describe the mutation-rate heterogeneity in the CR. Our results reconcile the controversial rate estimates in the phylogenetic and familial studies; the fast sites prevail in the latter, whereas the slow and moderate sites dominate the phylogenetic-rate estimations.

Canada↗
PubMed2001

Fragmentation of the Québec population genetic pool (Canada): evidence from the genetic contribution of founders per region in the 17th and 18th centuries.

The 6 million French-Canadians of Québec derive from a relatively small number of founders. Consequently, some hereditary diseases, which may or may not present a worldwide distribution, have been detected in high frequency in this population. Several studies, however, indicate a nonuniform distribution of these diseases through the population, suggesting that the French-Canadian founder effect has been geographically stratified. Here we explore this stratification by using a demographic database, the Population Register of Early Québec, that contains almost all birth, marriage, and death certificates (>712,000) recorded in parish registers between 1608-1800. In this database, every genealogical link has been traced back to the founders of the population, so that we can compute the genetic contribution of founder per region, and then account for the early events that have shaped the distribution of diseases. Ten regions, comprising varying numbers of parishes, have been selected. We first describe each region in terms of homogeneity and concentration of its gene pool. For this purpose, a new concept is introduced, the founders' uniform contribution number (FUN), i.e., the number of founders a population would have if all its founders had an equal contribution. Second, we estimate genetic similarity between regions on the basis of differential genetic contribution. To classify the regions, we use principal component and cluster analysis. Our results show a tripartite clustering of the population, and invite us to reconsider the results obtained from biomolecular and clinical studies, which show a bipartite clustering.

Adult↗
PubMed2001

The relationship between Y chromosome DNA haplotypes and Y chromosome deletions leading to male infertility.

Microdeletions on the short arm of the Y chromosome have defined three non-overlapping regions (AZFa, b, c) recurrently deleted among infertile males. These regions contain several genes or gene families involved in male germ-cell development and maintenance. Even though a meiotic origin for these microdeletions is assumed, the mechanisms and causes leading to microdeletion formation are largely unknown. In order to assess whether some Y chromosome groups (or haplogroups) are predisposed to, or protected against, deletion formation during male meiosis, we have defined and compared Y chromosome haplogroup distribution in a group of infertile/subfertile males harbouring Yq deletions and in a relevant Northwestern European control population. Our analyses suggest that Y chromosome deletion formation is, at least in the study populations, a stochastic event independent of the Y chromosome background on which they arise and may be caused by other genetic and/or environmental factors.

Chromosome Deletion↗
PubMed2000

Allelic association is increased by correlation of effective family size.

In a previous study, we showed that the observation of high frequencies of certain inherited disorders in the population of Saguenay Lac Saint Jean (SLSJ) in Quebec can be explained in terms of the variance and the auto-correlation of effective family size (EFS) across generations. Correlated EFS, across generations, allows alleles introduced as a single copy to reach very high frequencies in about 12 generations. Here, we investigate the impact of this same demographic process on allelic association between a disease locus and closely linked neutral markers. We model the fate of a disease allele, introduced as a single copy, and of its surrounding haplotype. We show that the auto-correlation of EFS across generations increases the expected proportion of individuals who carry the ancestral haplotype in the present generation. Thus, the length of a shared haplotype is longer, making this population useful for coarse mapping. But this autocorrelation decreases the estimated value; thus ignoring the auto-correlation in EFS leads to an underestimate of the recombination rate. This result is of importance, since socio-demographic processes such as auto-correlation of EFS across generations have been described in other human populations.

Alleles↗
PubMed1999

Impact of demographic distribution and population growth rate on haplotypic diversity linked to a disease gene and their consequences for the estimation of recombination rate: example of a French Canadian population.

A disease gene introduced into a rapidly growing population by a single individual remains in strong linkage disequilibrium with the surrounding molecular markers. Mapping strategies taking advantage of this phenomenon allow increased mapping resolution as compared to pedigree analysis. Demographic models underlying these strategies usually assume the population exponential growth approximated by Poisson distribution of the number of children per individual. Knowing the real demographic distribution in the studied French-Canadian population, we analyzed the validity of the Poisson approximation. We adapted the existing model of the Poisson branching process to the case of a rapidly growing population and to non-Poisson distributions. In consequence, we were able to apply maximum-likelihood methods to estimate the recombination rate under various demographic scenarios. Our analysis shows that the growth rate has a higher impact on the estimation of recombination rate than the shape of the demographic distribution. The choice of the demographic model (Poisson vs. non-Poisson) has little effect on the estimation of the recombination rate but affects the expected distribution of haplotype frequencies. This distribution, however, depends much more on the population growth rate. Finally, we also demonstrate the usefulness of the Luria-Delbrück method, which gives a correct estimation of the recombination rate in a growing population, provided the sampling error is taken into account in the confidence intervals.

Confidence Intervals↗
PubMed1999

A genealogical study of Alzheimer disease in the Saguenay region of Quebec.

We performed an analysis of inbreeding and kinship among the ascending genealogies of 205 autopsy-confirmed Alzheimer disease (AD) subjects recruited in the Saguenay area of Québec. We hypothesized that if some traits pertaining to the disease were determined by inherited factors, and if the corresponding genes were not too frequent in the population, it might be possible to detect some clusters of patients related to common ancestors and presenting a level of kinship and/or inbreeding higher than is observed in the unaffected population of the same age. In view of the heterogeneity of the disease, we also verified if some of the factors investigated could be associated more specifically with subsets of cases based on age of onset and on apolipoprotein E (APOE) genotype. Results were compared with those obtained on 205 controls matched for gender, place and year of birth. We found that late-onset AD cases with an APOE-epsilon 4 were significantly more inbred than controls and that this increase was explained by the high level of inbreeding of a few cases whose parents were related at the first-cousin level. This could possibly indicate the implication of a recessive element in a small subset of AD cases in the Saguenay population. We also found that late-onset epsilon 4+ cases were significantly more closely related among themselves than with controls. This increase in kinship may be attributable to the presence of the epsilon 4 allele or to some other unidentified genetic factor possibly acting in conjunction with APOE-epsilon 4.

Age of Onset↗
PubMed1999

Y-chromosome-specific microsatellite mutation rates re-examined using a minisatellite, MSY1.

Polymorphic Y-chromosome-specific microsatellites are becoming increasingly used in evolutionary and forensic studies and, in particular, in dating the origins of Y-chromosomal lineages. Previously, haplotyping of Y chromosomes from males belonging to a set of deep-rooting pedigrees was used to estimate a conservative average Y-chromosomal microsatellite mutation rate of 2.1 x 10(-3)per locus per generation. A number of males showed multiple differences in haplotypes compared with other males within their pedigrees, and these were excluded from the calculation of this estimate, on the grounds that non-paternity was a more probable explanation than multiple mutation within a lineage. Here we reanalyse the pedigrees using an independent highly polymorphic system, the Y-specific minisatellite, MSY1. This supports the hypothesis of non-paternity where more than one microsatellite difference was observed, provides further support for the previously deduced microsatellite mutation rate and throws light on the mutation dynamics of MSY1 itself, suggesting that single-step changes are not the only mode of mutation.

Genetic Markers↗
PubMed1999

One founder/one gene hypothesis in a new expanding population: Saguenay (Quebec, Canada).

High frequencies of some rare inherited recessive disorders can be found in the Saguenay region of Quebec, Canada. Four disorders have a carrier frequency of about 0.04 (in the range 0.035-0.05): pseudovitamin D-dependent rickets, hereditary tyrosinemia type 1, Charlevoix-Saguenay spastic ataxia, and sensorimotor polyneuropathy with or without agenesis of the corpus callosum. Molecular data suggest that only 1 mutation has been introduced into the population since its founding in the 17th century. The carrier frequencies are much higher than one would expect under a theoretical model that includes variance in family size and population growth (Thompson and Neel 1978). I present a methodology called allele dropping to test the hypothesis that only 1 founder introduced a given mutation. This study is based on 891 ascending genealogies and enables one to measure the extent of allele frequency changes resulting from the demographic history of the population. Two scenarios are tested: neutral and lethal alleles. Lethality has a minor effect because the alleles never reach a frequency high enough for selection to be strong. Twenty-five founders have a probability greater than 1% that a lethal mutation they introduced into the population will reach a carrier frequency between 0.035 and 0.05 in the contemporary population. Moreover, 2 founders have a probability greater than 20% that a lethal allele they introduced into the population will reach this target frequency. Therefore the simplest hypothesis that 1 founder introduced 1 disorder into the population is consistent.

Chi-Square Distribution↗
PubMed1998

Social transmission of reproductive behavior increases frequency of inherited disorders in a young-expanding population.

The observation of high frequencies of certain inherited disorders in the population of Saguenay-Lac Saint Jean can be explained in terms of the variance and the correlation of effective family size (EFS) from one generation to the next. We have shown this effect by using the branching process approach with real demographic data. When variance of EFS is included in the model, despite its profound effect on mutant allele frequency, any mutant introduced in the population never reaches the known carrier frequencies (between 0.035 and 0.05). It is only when the EFS correlation between generations is introduced into the model that we can explain the rise of the mutant alleles. This correlation is described by a c parameter that reflects the dependency of children's EFS on their parents' EFS. The c parameter can be considered to reflect social transmission of demographic behavior. We show that such social transmission dramatically reduces the effective population size. This could explain particular distributions in allele frequencies and unusually high frequency of certain inherited disorders in some human populations.

Female↗
PubMed1997

Estimating Y chromosome specific microsatellite mutation frequencies using deep rooting pedigrees.

Recently, a set of highly polymorphic chromosome Y specific microsatellites became available for forensic, population genetic and evolutionary studies. However, the lack of a mutation frequency estimate for these loci prevents a reliable application. We therefore used seven chromosome Y tetranucleotide repeat loci to screen 42 males who are descendants from 12 'founding fathers' by a total number of 213 generations. As a result, we were able to estimate an average chromosome Y tetranucleotide mutation frequency of 0.20% (95% CIL 0.05-0.55). This closely matches the often cited Weber and Wong estimate of 0.21% for a set of autosomal tetranucleotide repeats. Expanding the set of microsatellites with two more loci (a tri- and a penta-nucleotide repeat locus) an average chromosome Y microsatellite mutation frequency of 0.21% (95% CIL 0.06-0.49) was found. These estimates suggest that microsatellites on the Y chromosome have mutation frequencies comparable to those on the autosomes. This supports the hypothesis that slippage-generated growth is the driving force behind the microsatellite variability.

Gene Frequency↗
PubMed1997

Seventeenth-century European origins of hereditary diseases in the Saguenay population (Quebec, Canada).

For over three decades much research has been devoted to the identification of founders who could have been the first carriers of different deleterious genes in the French Canadian population. In some cases this research led to an investigation of the European origins of these founders. Using up-to-date data on genealogical records of 673 probands (6 hereditary diseases) and 99 control group individuals born in the Saguenay region (Quebec, Canada), we show that it is difficult to identify a precise region where a deleterious gene could have originated. By taking several key factors into consideration (founders' genetic contribution, level of commonness, sex, birth year), we found many possible candidates for each disease, leading to various regions of origin in France (Aunis, Maine, Normandie, Orléanais, Perche, and other provinces) or outside France (British Isles, other European countries). Our results also showed notable differences between the origins of male and female founders. Furthermore, all founders common to at least 95% of the probands of a given disease were also common to 95% of the probands of at least one other disease; among these founders 29 were common to 95% or more of the probands of each group (including the control group).

Emigration and Immigration↗
PubMed1995

Genetic consequences of differential demographic behaviour in the Saguenay region, Québec.

Some rare inherited disorders are found with a high frequency in the population of the Saguenay region (Québec province, Canada, population 300,000). Inbreeding coefficients are too low to be an explanation for these high frequencies. In the first decades of settlement (1842-1870), most of the immigrants came from a small region called Charlevoix (east of Québec city). As most of the genetic disorders found in the Saguenay region are also found in the Charlevoix region, it is strongly suspected that the genes were introduced by these first settlers from Charlevoix. Using the BALSAC database (which contains linked information on the entire Saguenay population) to calculate the number of contemporary descendants and the genetic contribution of each founder to these descendants, we show that: (1) Founders who entered the population before 1870 contribute to 45% of the contemporary gene pool, despite the fact that they represent only 15% of all the 20,012 immigrants with descendants in the contemporary population (individuals born between 1950 and 1971). (2) Their genetic contribution is not homogenous in the contemporary population: 5% of the population have 100% of their gene pool coming from these first founders, while 10% have a zero to 5% contribution from these earliest founders. (3) Fifty percent of the genes introduced in the population were lost. (4) If only 68 immigrants among the first founders (2.0%) were carriers of the same gene, it could reach a frequency of 5% in the contemporary population, which is the frequency of most of the inherited disorders found in the population.

Alleles↗
PubMed1995

Variability of the genetic contribution of Quebec population founders associated to some deleterious genes.

Relatively high frequencies of some rare inherited disorders can be found in the Saguenay Region (Quebec). To understand this phenomenon, a research project on the 17th-century founder effect that led to the formation of French Canadians' gene pool is being carried out. The focus of this study is on founders who contributed to the Saguenay gene pool and who are related to contemporary probands suffering from any one of five hereditary diseases: cystic fibrosis, tyrosinemia, hemochromatosis, Charlevoix-Saguenay spastic ataxia, and sensorimotor polyneuropathia with or without agenesis of the corpus callosum. A control group has been added for comparison purposes. Altogether, 545 ascending genealogies have been reconstructed, using the Interuniversity Institute for Population Research's RETRO database, leading to > 2,500 founders. The genetic contribution of each founder to each group has been measured. Results show that (1) nearly 80% of the individuals' gene pool come from founders who settled in Nouvelle-France in the 17th century, whatever the group; (2) 15% of the founders explain 90% of the total genetic contribution of the founders, but this pattern varies from one group to another; (3) there is no subgroup of founders more related to any given group of individuals.

Genes↗
PubMed1995

Mitochondrial and nuclear genetic contribution of female founders to a contemporary population in northeast Quebec.

A common challenge in population genetics is to reconstruct the evolutionary history of populations on the basis of current allele frequencies. Through pedigree analysis, we have the opportunity to study the genetic contribution of founders to the contemporary population. This contribution over many generations accounts for the probable introduction, survival, and extinction of genes in the population. I use this method to follow nuclear and mitochondrial genes in the Saguenay population of northeast Quebec by tracing back ascending genealogies of 160,315 individuals born between 1950 and 1971 by using the BALSAC database. This study leads us to conclude that even in a growing population, the loss rate of mtDNA is high. The survival of mtDNA in the population is independent of the time of introduction in the population. The number of copies of a particular mtDNA gene in the contemporary population is higher for genes introduced earlier, but the correlation between these two variables is low (the relation is not linear). Compared to nuclear contribution, mitochondrial contribution is higher, but the loss rate of nuclear DNA is lower. The differential contribution (the fact that few founders contribute a lot) is the same proportion for nuclear and mtDNA, but only 592 female founders contribute 50% of the mtDNA gene pool of the contemporary cohort, compared to 994 for nuclear DNA. Since we have no molecular data on founders' haplotypes, these results cannot give us the diversity level in the population. However, this study enables us to compare the evolutionary fates of nuclear and mitochondrial genes in this expanding population.

Biological Evolution↗
PubMed1991

Intervals between marriage and first birth in mothers and daughters.

Marriage-first birth intervals are examined in two historical populations, Quebec (1608-1765) and Haut-Jura (1689-1980), comparing intervals in mothers and daughters, and in sister-sister pairs. The results point to a weak relationship between intervals of mothers and daughters, though it does not attain significance. Shared environment does not seem to be responsible since there is no association between pairs of sisters from the same populations.

Adolescent↗