Genetic diversity of four Filipino negrito populations from Luzon: comparison of male and female effective population sizes and differential integration of immigrants into Aeta and Agta communities.

Genetic data corresponding to four negrito populations (two Aeta and two Agta; n = 120) from the Luzon region of the Philippines have been analyzed. These data comprise mitochondrial DNA (mtDNA) hypervariable segment 1 haplotypes and haplogroups, Y-chromosome haplogroups and short tandem repeats (STRs), autosomal STRs, and X-chromosome STRs. The genetic diversity and structure of the populations were investigated at a local, regional, and interregional level. We found a high level of autosomal differentiation, combined with no significant reduction in diversity, consistent with long-term settlement of the Luzon region by the ancestors of the Agta and Aeta followed by reduced gene flow between these two ethnolinguistic groups. Collectively, the Aeta have a much higher ratio of female:male effective population size than do the Agta, a finding that supports phylogenetic analysis of their mtDNA and Y-chromosome haplogroups, which suggests different genetic sex-biased contributions from putative Austronesian source populations. We propose that factors of social organization that led to the reduction in Agta female effective population size may also be linked to the limited incorporation of female lineages associated with the settlement of the Philippines by Austronesian speakers; conversely, the reduction in Aeta male effective population size, relative to females, could be indicative of a limited incorporation of male lineages associated with this demographic process.

Sex-specific demographic behaviours that shape human genomic variation.

In the human species, the two uniparental genetic systems (mitochondrial DNA and Y chromosome) exhibit contrasting diversity patterns. It has been proposed that sex-specific behaviours, and in particular differences in migration rate between men and women, may explain these differences. The availability of high-density genomic data and the comparison of genetic patterns on autosomal and sex chromosomes at global and local scales allow a reassessment of the extent to which sex-specific behaviours shape our genome. In this article, we first review studies comparing the genetic patterns at uniparental and biparental genetic systems and assess the extent to which sex-specific migration processes explain the differences between these genetic systems. We show that differences between male and female migration rates matter, but that they are certainly not the only contributing factor. In particular, differences in effective population size between men and women are also likely to account for these differences. Then, we present and discuss three anthropological processes that may explain sex-specific differences in effective population size and thus human genomic variation: (i) variance in reproductive success arising from, for example, polygyny; (ii) descent rules; and (iii) transmission of reproductive success.

Elevation of monocyte chemoattractant protein-1 in patients experiencing neurocognitive decline following carotid endarterectomy.

BACKGROUND: Previous studies have demonstrated that elevated pre-operative monocyte count is an independent predictor of acute neurocognitive decline following carotid endarterectomy (CEA). Monocyte chemoattractant protein-1 (MCP-1), secreted by human endothelial and monocyte-like cells, is a potent mediator of inflammation and mononuclear cell trafficking. This study examines the relationship between peri-operative serum MCP-1 elevation and post-operative neurocognitive injury following CEA. METHODS: Fifty-two patients undergoing CEA and 67 lumbar laminectomy (LL) controls were administered a battery of five neuropsychological tests pre-operatively and on post-operative day 1 (POD 1). Change in individual test scores from baseline to POD 1 were converted into Z-score and used to develop a point system quantifying the degree of neurocognitive dysfunction relative to change within the LL group. Neurocognitive injury following CEA was defined as a score greater than 2 standard deviations above mean total deficit scores of LL controls. Serum MCP-1 levels were measured pre-operatively and on POD 1 by enzyme-linked immunosorbent assay. FINDINGS: Mean percent MCP-1 elevation was higher for the 13 injured CEA patients (147.7 +/- 32.4%) in our cohort compared to 39 age- and sex-matched uninjured CEA patients (76.0 +/- 16.5%). In unconditional multivariate logistic regression analysis, percent elevation in serum MCP-1 level was associated with neurocognitive injury one day after CEA (OR = 2.19, 95% CI = 1.13-4.26, P = 0.021, for a 100% elevation from pre-operative levels). CONCLUSIONS: Peri-operative elevations in serum MCP-1 levels correlate with acute neurocognitive dysfunction following CEA. These data implicate an inflammatory mechanism in the pathogenesis of Ischaemic neurocognitive decline.

The effect of maternal care on child survival: a demographic, genetic, and evolutionary perspective.

Models of population dynamics generally assume that child survival is independent of maternal survival. However, in humans, the death of a mother compromises her immature children's survival because children require postnatal care. A child's survival therefore depends on her mother's survival in years following her birth. Here, we provide a model incorporating this relationship and providing the number of children surviving until maturity achieved by females at each age. Using estimates of the effect that a mother's death has on her child's survival until maturity, we explore the effect of the model on population dynamics. Compared to a model that includes a uniform child survival probability, our model slightly raises the finite rate of increase lambda and modifies generation time and the stable age structure. We also provide estimates of selection on alleles that change the survival of females. Selection is higher at all adult ages in our model and remains significant after menopause (at ages for which the usual models predict neutrality of such alleles). Finally, the effect of secondary caregivers who compensate maternal care after the death of a mother is also emphasized. We show that allocare (as an alternative to maternal care) can have a major effect on population dynamics and is likely to have played an important role during human evolution.

Unbiased interpretation of haplotypes at duplicated microsatellites.

The Y-chromosome is a powerful tool for population geneticists to study human evolutionary history. Haploid and largely non-recombining, it should contain a simple record of past mutational events. However, this apparent simplicity is compromised by Y-linked duplicons, which make up approximately 35% of this chromosome; 25% of these duplicons are large inverted repeats (palindromes). For microsatellites lying in these palindromes, two loci cannot be easily distinguished due to PCR co-amplification, and this order misspecification of alleles generates an additional variance component. Due to this ambiguity, population geneticists have traditionally used an arbitrary method to assign the alleles (shorter allele to locus 1, larger allele to locus 2). Here, we simulate these posterior estimate distributions under three different novel allele assignment priors and compare this with the original method. We use a sample of 33 human populations, typed for duplicated microsatellites lying within palindrome P8, to illustrate our approach. We show that both intra- and inter-population statistics can be dramatically affected by order misspecification. Surprisingly, matrices of pairwise F-statistics or distance estimates appear far less sensitive to order misspecification and remain relatively unchanged under the priors considered, suggesting that these microsatellites can be considered as useful markers for population genetic studies using an appropriate data treatment. Duplicated microsatellites represent an attractive source of information to investigate the extensive structural polymorphism observed among human Y chromosomes, as well as processes of intra-chromosomal gene conversion acting between duplicons.

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.

APOE-epsilon4 predisposes to cognitive dysfunction following uncomplicated carotid endarterectomy.

BACKGROUND: Between 9% and 23% of patients undergoing otherwise uncomplicated carotid endarterectomy (CEA) develop subtle cognitive decline 1 month postoperatively. The APOE-epsilon4 allele has been associated with worse outcome following stroke. OBJECTIVE: To investigate the ability of APOE-epsilon4 to predict post-CEA neurocognitive dysfunction. METHODS: Seventy-five patients with CEA undergoing elective CEA were prospectively recruited in this nested cohort study and demographic variables were recorded. Patients were evaluated before and 1 month after surgery with a standard battery of five neuropsychological tests. APOE genotyping was performed by restriction fragment length polymorphism analysis in all patients. Neuropsychological deficits were identified by comparing changes (before to 1 month post-operation) in individual performance on the test battery. Logistic regression was performed for APOE-epsilon4 and previously identified risk factors. RESULTS: Twelve of 75 (16%) CEA patients possessed the APOE-epsilon4 allele. Eight of 75 (11%) patients experienced neurocognitive dysfunction on postoperative day 30. One month post-CEA, APOE-epsilon4-positive patients were more likely to be cognitively injured (42%) than APOE-epsilon4-negative patients (5%) (p = 0.002). In multivariate analysis, the presence of the APOE-epsilon4 allele increased the risk of neurocognitive dysfunction at 1 month 62-fold (62.28, 3.15 to 1229, p = 0.007). Diabetes (51.42, 1.94 to 1363, p = 0.02), and obesity (24.43, 1.41 to 422.9, p = 0.03) also predisposed to injury. CONCLUSION: The APOE-epsilon4 allele is a robust independent predictor of neurocognitive decline 1 month following CEA.

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.

Sex-based differences in serum cardiac troponin I, a specific marker for myocardial injury, after cardiac surgery.

BACKGROUND: Prevalence and causes of sex-based differences in morbidity and mortality secondary to cardiovascular disease remain controversial. Cardiac troponin I (cTnI) is a sensitive and specific marker for myocardial injury. Serial cTnI measurements have been used to identify perioperative myocardial cell injury. OBJECTIVE: To determine whether sex influences the extent of myocardial injury during cardiac surgery, we measured perioperative cTnI in male and female patients. DESIGN: A total of 17 male and 17 female patients were prospectively studied in an age- and case-matched manner. Arterial cTnI were obtained preinduction, 30 mins after the application of the aortic cross-clamp, at arrival to the intensive care unit, and on postoperative day 1. SETTING: Tertiary cardiac surgery center at a major teaching hospital. RESULTS: There was no difference between men and women in body mass index (kg/m2), duration of cardiopulmonary bypass, and aortic cross-clamp times. Preoperative cTnI measurements were similar in men (0.24 +/- 0.15 ng/mL) and women (0.25 +/- 0.13 ng/mL, mean +/- sem). The maximum serum cTnI occurred on postoperative day 1 in all patients, and it was 3-fold higher in men (18.5 +/- 5.7 ng/mL) compared with women (6.4 +/- 1.0 ng/mL). CONCLUSIONS: Men had markedly higher serum cTnI compared with women, although they were case matched with respect to age and cardiac risk factors. Our results may suggest there may be sex-related differences in the myocardial response to ischemia and reperfusion injury or intrinsic differences between the male and female myocardium.

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.

Intergenerational correlation of effective family size in early Québec (Canada).

The use of a comprehensive demographic database of the early French Canadian population (1608-1800) reveals an almost null impact of parents' fertility on children's fertility (r approximately 0.01-0.05), which contradicts the commonly held view that family size has a tendency to run in families. However, in this population, there is a clear transmission from one generation to the next of the effective family size within a given geographical area (EFS, defined as the number of children that settle per settled individual). Three types of correlations between EFS of parents and children are presented in order to account for the impact of socio-demographic differentials. Individuals who belong to a large sibship and who settled in a given subdivision tend to encourage the settlement of a high number of their own children in the same subdivision (r approximately 0.1-0.3). An additional correlation was introduced to see if geographically-based differentials of EFS can account for the differential of founders' regional genetic contribution. The analysis shows that EFS correlation has a definite impact on the concentration of a population's gene pool (it increases it by approximately 20%-45%), and partly accounts for the differences between subdivisions in this regard.

Cardiac surgical patients exposed to heparin-bonded circuits develop less postoperative cerebral dysfunction than patients exposed to non-heparin-bonded circuits.

A prospective randomized trial was used to study the incidence of cerebral dysfunction in patients undergoing cardiopulmonary bypass (CPB) with heparin-bonded vs non-heparin-bonded circuits. Although the etiology of postoperative cerebral dysfunction is controversial, activation of the systemic inflammatory response may play a role. After institutional approval and informed written consent, 39 elective coronary artery bypass (CABG) patients were studied. A battery of neuropsychometric tests (NPMTs) was performed preoperatively, and 5 days and 6 weeks postoperatively. Significant change in NPMT performance was defined as a 25% or greater decrease in postoperative performance, compared to baseline. The number of abnormal tests per patient was calculated. Analysis using the Mann-Whitney rank test was performed for the first follow-up. Patients randomized to heparin-bonded circuits had fewer abnormal NPMTs (>1 abnormal test) on postoperative day 5 (58 vs 70%, n=19 and 20) than patients randomized to non-heparin-bonded circuits. Patients exposed to heparin-bonded circuits had fewer abnormal tests (>1 abnormal test) at 6 weeks (36 vs 63%, n=14 and 16). Results suggested that the attenuation of systemic inflammation by heparin-bonded CPB circuits may lower the incidence of cerebral injury in cardiac surgical patients.

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.

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.

Serum S100B protein levels are correlated with subclinical neurocognitive declines after carotid endarterectomy.

OBJECTIVE: Carotid endarterectomy (CEA) is an effective means of stroke prevention among appropriately selected patients; however, neuropsychometric testing has revealed subtle cognitive injuries in the early postoperative period. The purpose of this study was to establish whether serum levels of two biochemical markers of cerebral injury were correlated with postoperative declines in neuropsychometric test performance after CEA. METHODS: Fifty-five consecutive patients underwent a battery of neuropsychometric tests 24 hours before and 24 hours after elective CEA. Two patients were excluded because of postoperative strokes. The pre- and postoperative serum levels of S100B protein and neuron-specific enolase for injured patients, defined as those who exhibited significant declines in neuropsychometric test performance (n = 12), were compared with the levels for uninjured patients (n = 41). RESULTS: There were no significant differences in the baseline S100B levels for the two groups. Injured patients exhibited significantly higher S100B levels, compared with uninjured patients, at 24, 48, and 72 hours after surgery (P < 0.05). There were no significant differences in neuron-specific enolase levels for injured and uninjured patients at any time point. CONCLUSION: These data suggest that subtle cerebral injuries after CEA, even in the absence of overt strokes, are associated with significant increases in serum S100B but not neuron-specific enolase levels. Analyses of earlier time points in future studies of subtle cognitive injuries and biochemical markers of cerebral injury after CEA may be revealing.

Severe pain confounds neuropsychological test performance.

There is little information on the effect of pain on neuropsychological test performance. We have undertaken this study to explore which tests are affected by pain, the magnitude of these changes, and other confounders of neuropsychological performance in a population of patients having spine surgery. Twenty-four elderly English speaking Caucasian patients (age > 60 years) were enrolled pre-operatively in this Institutional Review Board approved study. Pain scores using an 11-point Numeric Pain Intensity scale and performance on a neuropsychological battery (Controlled Oral Word Association, Rey Complex Figure, Trails A and B) were assessed at two times, before and one day after surgery. Scores were calculated using the standard algorithms and change scores were calculated by subtracting the baseline from follow-up scores. After surgery, performance on the Rey Complex Figure ( r = -0.577, p = 0.004) and Trails Part A (r = 0.527, p = 0.01) declined with increasing post-operative pain scores. Women reported higher pain scores post-operatively than men (p = 0.046), and performed worse than men for change in performance on Trails Part A (p = 0.027). These data suggest that pain can influence performance on certain cognitive tests, and that some gender differences in these effects may occur. Interpretation of performance measures should take into account possible effects of pain, although our understanding of pain effects and ability to predict them in individual people, currently are quite limited.