Vincenzo Lorenzo Pascali

Discerning the ancestry of European Americans in genetic association studies

European Americans are often treated as a homogeneous group, but in fact form a structured population due to historical immigration of diverse source populations. Discerning the ancestry of European Americans genotyped in association studies is important in order to prevent false-positive or false-negative associations due to population stratification and to identify genetic variants whose contribution to disease risk differs across European ancestries. Here, we investigate empirical patterns of population structure in European Americans, analyzing 4,198 samples from four genome-wide association studies to show that components roughly corresponding to northwest European, southeast European, and Ashkenazi Jewish ancestry are the main sources of European American population structure. Building on this insight, we constructed a panel of 300 validated markers that are highly informative for distinguishing these ancestries. We demonstrate that this panel of markers can be used to correct for stratification in association studies that do not generate dense genotype data.

DNA Commission of the International Society of Forensic Genetics: recommendations on forensic analysis using Y- chromosome STRs

During the past few years the DNA commission of the International Society of Forensic Genetics has published a series of documents providing guidelines and recommendations concerning the application of DNA polymorphisms to the problems of human identification. This latest report addresses a relatively new area, namely Y-chromosome polymorphisms, with particular emphasis on short tandem repeats (STRs). This report addresses nomenclature, use of allelic ladders, population genetics and reporting methods.

A predominantly neolithic origin for Y-chromosomal DNA variation in North Africa.

We have typed 275 men from five populations in Algeria, Tunisia, and Egypt with a set of 119 binary markers and 15 microsatellites from the Y chromosome, and we have analyzed the results together with published data from Moroccan populations. North African Y-chromosomal diversity is geographically structured and fits the pattern expected under an isolation-by-distance model. Autocorrelation analyses reveal an east-west cline of genetic variation that extends into the Middle East and is compatible with a hypothesis of demic expansion. This expansion must have involved relatively small numbers of Y chromosomes to account for the reduction in gene diversity towards the West that accompanied the frequency increase of Y haplogroup E3b2, but gene flow must have been maintained to explain the observed pattern of isolation-by-distance. Since the estimates of the times to the most recent common ancestor (TMRCAs) of the most common haplogroups are quite recent, we suggest that the North African pattern of Y-chromosomal variation is largely of Neolithic origin. Thus, we propose that the Neolithic transition in this part of the world was accompanied by demic diffusion of Afro-Asiatic-speaking pastoralists from the Middle East.

A Predominantly Indigenous Paternal Heritage for the Austronesian-Speaking Peoples of Insular Southeast Asia and Oceania

Modern humans reached Southeast Asia and Oceania in one of the first dispersals out of Africa. The resulting temporal overlap of modern and archaic humans-and the apparent morphological continuity between them-has led to claims of gene flow between Homo sapiens and H. erectus. Much more recently, an agricultural technology from mainland Asia spread into the region, possibly in association with Austronesian languages. Using detailed genealogical study of Y chromosome variation, we show that the majority of current Austronesian speakers trace their paternal heritage to Pleistocene settlers in the region, as opposed to more-recent agricultural immigrants. A fraction of the paternal heritage, however, appears to be associated with more-recent immigrants from northern populations. We also show that the northern Neolithic component is very unevenly dispersed through the region, with a higher contribution in Southeast Asia and a nearly complete absence in Melanesia. Contrary to claims of gene flow (under regional continuity) between H. erectus and H. sapiens, we found no ancestral Y chromosome lineages in a set of 1,209 samples. The finding excludes the possibility that early hominids contributed significantly to the paternal heritage of the region.

Probabilistic Expert Systems for Forensic Inference from Genetic Markers

We present a number of real and fictitious examples in illustration of a new approach to analysing complex cases of forensic identification inference. This is effected by careful restructuring of the relevant pedigrees as a Probabilistic Expert System. Existing software can then be used to perform the required inferential calculations. Specific complications which are readily handled by this approach include missing data on one or more relevant individuals, and genetic mutation. The method is particularly valuable for disputed paternity cases, but applies also to certain criminal cases.

DNA commission of the International Society of Forensic Genetics: Recommendations on forensic analysis using Y-chromosome STRs

Abstract During the past few years the DNA commission of the International Society of Forensic Genetics has published a series of documents providing guidelines and recommendations concerning the application of DNA polymorphisms to the problems of human identification. This latest report addresses a relatively new area, namely Y-chromosome polymorphisms, with particular emphasis on short tandem repeats (STRs). This report addresses nomenclature, use of allelic ladders, population genetics and reporting methods.

The Analysis of Variation of mtDNA Hypervariable Region 1 Suggests That Eastern and Western Pygmies Diverged before the Bantu Expansion

The Eastern Pygmies from Zaire and Western Pygmies from Cameroon, Congo, and the Central African Republic represent the two principal groups of African Pygmies. In the “recent divergence” hypothesis in which Western Pygmies are thought to be the result of hybridization between the ancestors of Eastern Pygmies and Bantu farmers who penetrated the equatorial belt and came into contact with Pygmies around 2–3 kiloyears ago. On the basis of recent archaeological research in the tropical rain forest, we propose a “pre‐Bantu divergence” hypothesis, which posits the separation between the ancestors of Eastern and Western Pygmies earlier than 18 kiloyears ago. In order to test the two hypotheses, we analyzed the variation of the hypervariable region 1 of the mitochondrial DNA in the Mbenzele, Western Pygmies of the Central African Republic, and compared our results with those of previous mtDNA and Y chromosome studies. Distribution, sequence variation, and age of haplogroups along with genetic distances among populations, estimates of divergence times, and simulations based on the coalescent approach were found to be congruent with the pre‐Bantu divergence but failed to support the recent divergence hypothesis.

Coordinating Y-chromosomal STR research for the courts

The growing interest of contemporary biology in the human Y chromosome (Hammer 1995; Jobling and TylerSmith 1995) has extended to forensic circles. This trend emerges from a consideration of the increasing number of papers published in forensic science journals concerned in qualifying polymorphisms of human Y chromosomes as tools for molecular identification. Jobling et al. (1997) list a number of forensic issues to which the male-specific profiles could be applied and discuss their appropriateness and suitability. In view of the inherent court application, we wish to discuss some critical aspects of this new class of DNA profiles and issue some guidelines for those researchers who are considering to prepare and submit forensic YSTR work to the International Journal of Legal Medicine.

Non-fatherhood or mutation? A probabilistic approach to parental exclusion in paternity testing

The occurrence of germline mutations at microsatellite loci poses problems in ascertaining non-fatherhood status in paternity testing. We describe the appropriate probabilistic analysis for computing the likelihood ratio in favour of paternity while allowing for mutation, for all 18 relevant combinations of seemingly incompatible parental genotypes. We allow arbitrary and possibly different mutation rates in paternal and maternal germlines. We describe a stationary mutation model for expressing the required allele-specific transition mutation rates in terms of overall mutation rates, and compare the likelihood ratios calculated from this and from other mutation models suggested in the literature. We also show how to derive an upper bound on the likelihood ratio, depending only on the overall mutation rate.

State of the art in forensic investigation of sudden cardiac death.

The sudden death of a young person is a devastating event for both the family and community. Over the last decade, significant advances have been made in understanding both the clinical and genetic basis of sudden cardiac death. Many of the causes of sudden death are due to genetic heart disorders, which can lead to both structural (eg, hypertrophic cardiomyopathy) and arrhythmogenic abnormalities (eg, familial long QT syndrome, Brugada syndrome). Most commonly, sudden cardiac death can be the first presentation of an underlying heart problem, leaving the family at a loss as to why an otherwise healthy young person has died. Not only is this a tragic event for those involved, but it also presents a great challenge to the forensic pathologist involved in the management of the surviving family members. Evaluation of families requires a multidisciplinary approach, which should include cardiologists, a clinical geneticist, a genetic counselor, and the forensic pathologist directly involved in the sudden death case. This multifaceted cardiac genetic service is crucial in the evaluation and management of the clinical, genetic, psychological, and social complexities observed in families in which there has been a young sudden cardiac death. The present study will address the spectrum of structural substrates of cardiac sudden death with particular emphasis given to the possible role of forensic molecular biology techniques in identifying subtle or even merely functional disorders accounting for electrical instability.