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Title: Age-Dependent Recombination Rates in Human Pedigrees}
Article:
Abstract:
In humans, chromosome-number abnormalities have been associated with altered recombination and increased maternal age. Therefore, age-related effects on recombination are of major importance, especially in relation to the mechanisms involved in human trisomies. Here, we examine the relationship between maternal age and recombination rate in humans. We localized crossovers at high resolution by using over 600, 000 markers genotyped in a panel of 69 French-Canadian pedigrees, revealing recombination events in 195 maternal meioses. Overall, we observed the general patterns of variation in fine-scale recombination rates previously reported in humans. However, we make the first observation of a significant decrease in recombination rates with advancing maternal age in humans, likely driven by chromosome-specific effects. The effect appears to be localized in the middle section of chromosomal arms and near subtelomeric regions. We postulate that, for some chromosomes, protection against non-disjunction provided by recombination becomes less efficient with advancing maternal age, which can be partly responsible for the higher rates of aneuploidy in older women. We propose a model that reconciles our findings with reported associations between maternal age and recombination in cases of trisomies.
Introduction:
Meiotic recombination is crucial in both driving the evolution of genomes and ensuring faithful segregation of pairs of homologous chromosomes during gametogenesis. The initiation of genetic recombination during the first meiotic prophase enables homologous chromosomes to orient properly on the spindle and helps form physical connections between chromosomes[1]. This process results in strand crossovers and further leads to zygotes harboring new combinations of parental genetic material. Every descendant is therefore provided with a unique mosaic of both pairs of parental chromosomes. In most mammals, including humans, there are important sex-differences in recombination rates and patterns[2]. First, the distribution of crossovers along the genome differs between sexes, tending to be lower at the telomeres in females relative to males[3]. Second, the average size of the genetic map for females is 1. 6 times longer than that for males[4],[5]. Third, 15% of female and male hotspots are sex-specific[6]. Evidence indicates that these differences result from sexual dimorphism in the regulation of the meiotic process[7]–[9], but high levels of heterogeneity in recombination rate is also observed within the same sex. Pedigree studies have identified extensive variation in rates among females[3],[4] and more recent studies reported significant variation in both female and male crossover rates[6],[9]–[11]. In addition to interindividual variation, the number of crossovers among different gametes of an individual has been reported to vary[12],[13]. However, variation in gamete recombination does not necessarily translate into variation in offspring recombination, since only a small subset of gamete variation may be consistent with live-born offspring. For example, more than 20% of oocytes exhibit an abnormal number of chromosomes, and yet very few aneuploid embryos are viable[7]. Since reduction or failure of meiotic recombination is associated with improper disjunction of chromosomes, leading to genetically unbalanced gametes, high rates of recombination protect oocytes from non-disjunction events[1],[14], and oocytes with many crossovers are likely to result in a live embryo. Conversely, oocytes exhibiting too few crossovers are particularly prone to aneuploidy. The most important factor linked to chromosomal aneuploidy in women is advancing maternal age[7]. Since very little is known about age-related causes of non-disjunction, it remains important to establish associations between patterns of recombination and maternal age in normal meioses. Although recombination is initiated during fetal development in mammal females, age can still influence recombination. In mice, it has been demonstrated that oocytes do not exit the mitotic phase of oogenesis all at once, but rather in successive waves[15]. Furthermore, oocytes ovulate in the same order in which they entered meiosis[15]. This ‘production line’ model thus suggests that eggs ovulated late in life are the result of more premeiotic mitotic divisions. Contradictory observations for relationships between maternal age and recombination rates have been reported in mammals, with studies reporting weak increases with age of recombination count estimates in humans[11],[16] whereas in mice and hamsters decreases in frequency of crossovers with age were reported[17],[18]. To further investigate the maternal age effect on recombination in humans, we densely genotyped individuals from 68 French-Canadian families in Quebec and localized recombination events at high resolution using a previously described method[11]. We report a significant genome-wide decrease in recombination rate with advancing maternal age in humans and we compare our results with observations from similar studies. Chromosome-specific effects likely drive the observed reduction in recombination with age. Our observations are consistent with a proposed model in which protection against non-disjunction through recombination becomes less efficient with advancing maternal age in some chrosomosomes.
Discussion:
In this study, we examined age-related effects on recombination and observed a negative correlation between the number of maternal crossovers and the mother's age at the time of birth. The proportion of the total variance explained by the genome-wide correlation is significant, yet relatively small( 8. 1%). This observation is striking considering no strong effect is expected, because considerably reduced levels of recombination are associated with non-viable offspring. The maternal-age effect is pronounced in the middle and distal portions of chromosomal arms. The decrease in recombination might be more pronounced for mothers younger then 32 years of age, after which the rate of maternal non-disjunction is reported to accelerate[7]. The possibility that age might influence recombination rates has been examined in several organisms. An age-related decline in recombination has been demonstrated in plants and Drosophila[30],[31]. However, in the latter an increase at older age( >16 days) has been reported[31],[32]. In mammals, while maternal age has been associated with recombination rate in several studies, paternal age effects on recombination have not been demonstrated. This asymmetry may be explained by important differences in the time of entry, duration and outcome of meiotic processes between sexes[7],[8]. While male germ cells are produced continuously and progress from prophase I to the second meiotic division in several days, the life cycle of oocytes is longer and more complex, beginning during early fetal life[33]. After a period of mitotic proliferation, oocytes progress through prophase I and initiate genetic recombination, before entering an arrest phase. In humans, meiotic arrest can be maintained for decades, until the oocyte resumes the first meiotic division and proceeds to metaphase II, prior to ovulation. In each of these meiotic stages, errors affecting chromosome segregation may occur and become more frequent as women age[34]. Particularly, the physical manifestation of recombination has a critical role in tethering homologous chromosomes together during meiosis[1], and a significant reduction in recombination has been identified as a causal mechanism underlying non-disjunction of pairs of chromosomes[13]. If the association we observe in this study reflects reduced recombination in oocytes ovulated later in life, one might consider this reduction to be partially responsible for higher level of aneuploidies in older women. While our results are in agreement with the effects reported in mammals, they directly contradict previous studies demonstrating recombination rates increase with maternal age in humans[2],[11],[16]. All other analyses we performed studying recombinational patterns among families, sexes and individuals corroborate results found in other cohorts. It is possible that fewer markers or possible misspecification of maternal ages at birth in the Icelandic cohrt contributed to differences in these studies. Furthermore, the effect of maternal age on recombination rate reported was very small[16]( 0. 043 crossovers per year). We showed that our effect, which is almost 10-times stronger in the opposite( negative) direction, would not have been detectable in our sample using a similar marker density and maternal age estimation[16]. Further analyses of the Icelandic cohort, using recently published data[6], may be informative. The positive correlation in the Hutterite cohort is also very weak, albeit significant[11]. Our data and methods are very similar and are unlikey to be the cause of the discrepancy. There may be two remaining explanations that can account for the differences between the two studies: either the populations are intrinsically different or the studies are capturing different aspects of variation in female recombination rates. It is possible that the different trends observed in these studies reflect a variable age phenotype in females[9],[19]. In humans, genetic determinants could have evolved to counter an age-related reduction in recombination, as it is observed in rodents, leading either to the absence or a weak increase of recombination rates[16]. If these phenotypes coexist in human populations, one may observe increasing, decreasing or even U-shaped trends in any given population. Moreover, the selective pressure acting in humans is unlikely to act in rodents, who rarely exhibit age-related meiotic dysfunctions, allowing the negative maternal age effect to be observed consistently. Because of the association between aneuploidy and recombination rates, women that do not harbor an « age-dependent reduction » recombination phenotype will tend to have more children later in life. This would lead to a potential slight increase in the mean number of recombinations for mothers having more children[11],[16]. We note that there are a greater proportion of larger families in both the Icelandic and the Hutterites cohorts compared to our cohort. If the risk of non-disjunction or other chromosomal anomalies increases with age, then only oocytes with more recombination will survive and be observed in larger families. The age-effect observed among French-Canadians may also be a consequence, and not a cause, of the higher frequencies of non-disjunction with advancing maternal age. The patterns we observed for viable offspring do not necessarily reflect a decrease of recombination among oocytes in the female ovary, where all eggs might be recombining at the same rate. Rather, the number of crossovers sufficient for proper homologous segregation in young women may not be protective against non-disjunction in older women. More oocytes would give rise to aneuploid zygotes when ovulated later in life, a model consistent with the observations that increasing age of women increases the likelihood of trisomy. Under this hypothesis, one can show that the mean number of crossovers observed is expected to increase with maternal age in aneuploid conceptions and to decrease in normal, properly disjoined, fertilized eggs( Figure 4 and Text S1). Trisomy studies provide evidence that recombination rates may increase with maternal age in aneuploid conceptions. Robinson and colleagues[35] studied non-disjunctions of chromosome 15 and reported that the mean maternal age at birth for cases harboring more than two crossovers is substantially higher than for cases with zero, one or two crossovers. This suggests a positive association between maternal age and recombination rate in aneuploid conceptions involving chromosome 15, and similar associations have been reported for chromosomes 18 and X[36],[37]. In trisomy 13, 16 and 21, however, no age-effect was reported[38]–[41] except for one study in trisomy 21 which found such an effect[42]. Interestingly, in the normal conceptions studied here, chromosomes 15 and 18 had a significant decrease in recombination with maternal age, whereas no significant effects were found for chromosomes 13, 16 and 21. Therefore, our model is consistent with significant association found for some chromosomes but not for others[7],[43]. Not all trisomies are affected by increasing maternal age equally and it seems unlikely that the same mechanisms apply to all aneuploid conceptions[44]. Altogether, these data highlight the fact that different chromosomes are subjected to distinct selective, mechanistic or structural constraints influencing recombination patterns over successive generations. This points to chromosome-specific effects that might be critical determinants of the complex relationship between maternal age and recombination in humans. Chromosome-specific effects may vary among populations depending on genetic differences in factors regulating the recombination machinery. Our results support this hypothesis, as a significant decay was found on nine chromosomes in our French-Canadian cohort and on two chromosomes in the Hutterites. The result for chromosome 20 was significant in both cohorts, but the overlap could be explained by chance alone. Many factors could reduce the protection provided by recombination from meiotic breakdown, such as factors acting when meiosis resumes after arrest during the final stages of oocyte growth and maturation[45]–[47]. Furthermore, factors related to the functional significance of telomeres in meiotic recombination might be implicated. According to the telomere theory of reproductive aging in women[48],[49] shorter telomeres could be detrimental to segregation of chromosomes, especially for those with recombination event near subtelomeric regions[50],[51]. Moreover, the telomere length and rate of erosion might be associated with sex- and chromosome-specific genetic factors[52],[53] that vary among human populations or cohorts. In conclusion, high-density genotyping of nuclear families enabled us to capture individual heterogeneity in recombination rates. The results described here are in favor of adaptative theories of sex-specific recombination rates[2] suggesting that increased rates in females may have evolved to compensate for improper chiasma formations later in life. The biological causes that underlie recombinational variation and sex-differences have been under investigation[9],[19],[54],[55], but the implications of variable rates for population genetic inferences and disease mapping remain unknown.
Aging is a genetically and environmentally modulated process . One particular manifestation of aging in humans is the age-related changes that affect the female reproductive system . It is well established that chromosome-number abnormalities in offspring occur more frequently as maternal age advances , but the meiotic mechanisms involved remain unclear . Meiotic recombination has been associated with maternal age in different species but contrasting effects of maternal age on recombination rates have been reported among mammals . In this study , we found a decrease of recombination rates with increasing maternal age in a French-Canadian cohort , with the most pronounced decline possibly occurring before 32 years of age . We observed chromosome-specific age effects , and in older women recombination frequencies are notably reduced in the middle portion of chromosomal arms and near subtelomeric regions . No paternal age effect on recombination was found , highlighting differences in patterns of variation among sexes . Many studies have shown significant inter-individual variation in genome-wide recombination rates , and our results points to an additional , intra-individual source of variation in recombination rates among transmissions from the same mother .