Nonrecombining Y-chromosomal microsatellites (Y-STRs) are widely used to infer population histories, discover genealogical relationships, and identify males for criminal justice purposes. Although a key requirement for their application is reliable mutability knowledge, empirical data are only available for a small number of Y-STRs thus far. To rectify this, we analyzed a large number of 186 Y-STR markers in nearly 2000 DNA-confirmed father-son pairs, covering an overall number of 352,999 meiotic transfers. Following confirmation by DNA sequence analysis, the retrieved mutation data were modeled via a Bayesian approach, resulting in mutation rates from 3.78 × 10(-4) (95% credible interval [CI], 1.38 × 10(-5) - 2.02 × 10(-3)) to 7.44 × 10(-2) (95% CI, 6.51 × 10(-2) - 9.09 × 10(-2)) per marker per generation. With the 924 mutations at 120 Y-STR markers, a nonsignificant excess of repeat losses versus gains (1.16:1), as well as a strong and significant excess of single-repeat versus multirepeat changes (25.23:1), was observed. Although the total repeat number influenced Y-STR locus mutability most strongly, repeat complexity, the length in base pairs of the repeated motif, and the father's age also contributed to Y-STR mutability. To exemplify how to practically utilize this knowledge, we analyzed the 13 most mutable Y-STRs in an independent sample set and empirically proved their suitability for distinguishing close and distantly related males. This finding is expected to revolutionize Y-chromosomal applications in forensic biology, from previous male lineage differentiation toward future male individual identification.

Intergenerational time intervals are frequently used in human population-genetics studies concerned with the ages and origins of mutations. In most cases, mean intervals of 20 or 25 years are used, regardless of the demographic characteristics of the population under study. Although these characteristics may vary from prehistoric to historical times, we suggest that this value is probably too low, and that the ages of some mutations may have been underestimated. Analyses were performed by using the BALSAC Population Register (Quebec, Canada), from which several intergenerational comparisons can be made. Family reconstitutions were used to measure interval lengths and variations in descending lineages. Various parameters were considered, such as spouse age at marriage, parental age, and reproduction levels. Mother-child and father-child intervals were compared. Intergenerational male and female intervals were also analyzed in 100 extended ascending genealogies. Results showed that a mean value of 30 years is a better estimate of intergenerational intervals than 20 or 25 years. As marked differences between male and female interval length were observed, specific values are proposed for mtDNA, autosomal, X-chromosomal, and Y-chromosomal loci. The applicability of these results for age estimates of mutations is discussed.

Since their origin, human populations have colonized the whole planet, but the demographic processes governing range expansions are mostly unknown. We analyzed the genealogy of more than one million individuals resulting from a range expansion in Quebec between 1686 and 1960 and reconstructed the spatial dynamics of the expansion. We find that a majority of the present Saguenay Lac-Saint-Jean population can be traced back to ancestors having lived directly on or close to the wave front. Ancestors located on the front contributed significantly more to the current gene pool than those from the range core, likely due to a 20% larger effective fertility of women on the wave front. This fitness component is heritable on the wave front and not in the core, implying that this life-history trait evolves during range expansions.

Characterizing the genetic structure of worldwide populations is important for understanding human history and is essential to the design and analysis of genetic epidemiological studies. In this study, we examined genetic structure and distant relatedness and their effect on the extent of linkage disequilibrium (LD) and homozygosity in the founder population of Quebec (Canada). In the French Canadian founder population, such analysis can be performed using both genomic and genealogical data. We investigated genetic differences, extent of LD, and homozygosity in 140 individuals from seven sub-populations of Quebec characterized by different demographic histories reflecting complex founder events. Genetic findings from genome-wide single nucleotide polymorphism data were correlated with genealogical information on each of these sub-populations. Our genomic data showed significant population structure and relatedness present in the contemporary Quebec population, also reflected in LD and homozygosity levels. Our extended genealogical data corroborated these findings and indicated that this structure is consistent with the settlement patterns involving several founder events. This provides an independent and complementary validation of genomic-based studies of population structure. Combined genomic and genealogical data in the Quebec founder population provide insights into the effects of the interplay of two important sources of bias in genetic epidemiological studies, unrecognized genetic structure and cryptic relatedness.

Background and objective:In clinical settings with fixed resources allocated to predictive genetic testing for high-risk cancer predisposition genes, optimal strategies for mutation screening programmes are critically important. These depend on the mutation spectrum found in the population under consideration and the frequency of mutations detected as a function of the personal and family history of cancer, which are both affected by the presence of founder mutations and demographic characteristics of the underlying population. The results of multistep genetic testing for mutations in BRCA1 or BRCA2 in a large series of families with breast cancer in the French-Canadian population of Quebec, Canada are reported. Methods: A total of 256 high-risk families were ascertained from regional familial cancer clinics throughout the province of Quebec. Initially, families were tested for a panel of specific mutations known to occur in this population. Families in which no mutation was identified were then comprehensively tested. Three algorithms to predict the presence of mutations were evaluated, including the prevalence tables provided by Myriad Genetics Laboratories, the Manchester Scoring System and a logistic regression approach based on the data from this study. Results: 8 of the 15 distinct mutations found in 62 BRCA1/BRCA2-positive families had never been previously reported in this population, whereas 82% carried 1 of the 4 mutations currently observed in >2 families. In the subset of 191 families in which at least 1 affected individual was tested, 29% carried a mutation. Of these 27 BRCA1-positive and 29 BRCA2-positive families, 48 (86%) were found to harbour a mutation detected by the initial test. Among the remaining 143 inconclusive families, all 8 families found to have a mutation after complete sequencing had Manchester Scores >18. The logistic regression and Manchester Scores provided equal predictive power, and both were significantly better than the Myriad Genetics Laboratories prevalence tables (p,0.001). A threshold of Manchester Score >18 provided an overall sensitivity of 86% and a specificity of 82%, with a positive predictive value of 66% in this population. Conclusion: In this population, a testing strategy with an initial test using a panel of reported recurrent mutations, followed by full sequencing in families with Manchester Scores >18, represents an efficient test in terms of overall cost and sensitivity.