Fast and accurate kinship estimation using sparse SNPs in relatively large database searches

Forensic genetic genealogy (FGG) has primarily relied upon dense single nucleotide polymorphism (SNP) profiles from forensic samples or unidentified human remains queried against online genealogy database(s) of known profiles generated with SNP microarrays or from whole genome sequencing (WGS). In these queries, SNPs are compared to database samples by locating contiguous stretches of shared SNP alleles that allow for detection of genomic segments that are identical by descent (IBD) among biological relatives (kinship). This segment-based approach, while robust for detecting distant relationships, generally requires DNA quantity and/or quality that are sometimes not available in forensic casework samples. By focusing on SNPs with maximal discriminatory power and using an algorithm designed for a sparser SNP set than those from microarray typing, performance similar to segment matching was reached even in difficult casework samples. This algorithm locates shared segments using kinship coefficients in “windows” across the genome. The windowed kinship algorithm is a modification of the PC-AiR and PC-Relate tools for genetic relatedness inference, referred to here as the “whole genome kinship” approach, that control for the presence of unknown or unspecified population substructure. Simulated and empirical data in this study, using DNA profiles comprised of 10,230 SNPs (10K multiplex) targeted by the ForenSeq™ Kintelligence Kit demonstrate that the windowed kinship approach performs comparably to segment matching for identifying first, second and third degree relationships, reasonably well for fourth degree relationships, and with fewer false kinship associations. Selection criteria for the 10K SNP PCR-based multiplex and functionality of the windowed kinship algorithm are described.     

Forensic genealogy—A comparison of methods to infer distant relationships based on dense SNP data

The concept forensic genealogy was discussed already in 2005 but has recently emerged in relation to the use of public genealogy databases to find relatives of the donor of a crime stain. In this study we explored the results and evaluation of searches conducted in such databases. In particular, we focused on the statistical classification that entails from the search and study the variation observed for different relationship classes. The forensic guidelines advocate the use of the likelihood ratio (LR) as a mean to measure the weight of evidence, which requires exact formulation of competing hypotheses. We contrast the LR approach with alternative approaches relying on identical by state (IBS) measures to estimate the total length of shared genomic segments as well as identical by descent (IBD) coefficients for a pair of individuals.We used freely accessible data from the 1000 Genome project to perform extensive simulations, generating data for a number of distinct relationships. Specifically we studied some overarching relationship classes and the performance of the above-mentioned evaluative approaches to classify a known pair of relatives into each class.The results indicate that the traditional LR approach as a single source of classification is as good as, and in some cases even better than, the alternative approaches. In particular the true classification rate is higher for some distant relationship. However, the LR approach is both computer-intensive and sensitive to population frequencies as well as genetic maps (positions of the markers). We further showed that when combining different classification approaches, a lower false classification rate was achieved while still maintaining a high true classification rate.     

Clinical Variability of Stickler Syndrome : Role of Exon 2 of the Collagen COL2A1 Gene

Stickler syndrome (progressive arthro-ophthalmopathy) is a genetically heterogeneous disorder resulting from mutations in at least three collagen genes. The most common disease-causing gene is COL2A1, a 54-exon-containing gene coding for type II collagen. At least 17 different mutations causing Stickler syndrome have been reported in this gene. Phenotypically, it is also a variably expressed disorder in which most patients present with a wide range of eye and extraocular manifestations including auditory, skeletal, and orofacial manifestations. Some patients, however, present without clinically apparent systemic findings. This observation has led to difficulty distinguishing this Stickler phenotype from other hereditary vitreoretinal degenerations, such as Wagner syndrome and Snowflake vitreoretinal degeneration. In this regard, review of the literature indicates type II collagen exists in two forms resulting from alternative splicing of exon 2 of the COL2A1 gene. One form, designated as type IIB (short form), is preferentially expressed in adult cartilage tissue. The other form, designated as type IIA (long form), is preferentially expressed in the vitreous body of the eye. Because of this selective tissue expression, mutations in exon 2 of the COL2A1 gene have been hypothesized to produce this Stickler syndrome phenotype with minimal or absent extraocular findings. We review the evidence for families with exon 2 mutations of the collagen COL2A1 gene presenting in a distinct manner from families with mutations in the remaining 53 exons, as well as other hereditary vitreoretinal degenerations without significant systemic manifestations.     

The West Family Chiropractic Dynasty: celebrating a century of accomplishment in Canada: Part I: Archibald B. West,DC, Samuel H. West,DC and Stephen E. West,DC: The Founding Father,his Son and Grandson

This historical treatise documents the unbroken legacy of the West family of chiropractors which has flourished in Canada for over 100 years. Part I, unearths the origins, development and careers of Archibald West, the founder of this dynasty, his son Samuel and grandson Stephen. Part II, not yet ready for publication, will delve into the lives of Archibald’s brother Samson and his chiropractic progeny, as well as a nephew of Stephen and another relative of Frederick West.     

Rapid growth of a hepatocellular carcinoma and the driving mutations revealed by cell-population genetic analysis of whole-genome data

We present the analysis of the evolution of tumors in a case of hepatocellular carcinoma. This case is particularly informative about cancer growth dynamics and the underlying driving mutations. We sampled nine different sections from three tumors and seven more sections from the adjacent nontumor tissues. Selected sections were subjected to exon as well as whole-genome sequencing. Putative somatic mutations were then individually validated across all 9 tumor and 7 nontumor sections. Among the mutations validated, 24 were amino acid changes; in addition, 22 large indels/copy number variants (>1 Mb) were detected. These somatic mutations define four evolutionary lineages among tumor cells. Separate evolution and expansion of these lineages were recent and rapid, each apparently having only one lineage-specific protein-coding mutation. Hence, by using a cell-population genetic definition, this approach identified three coding changes (CCNG1, P62, and an indel/fusion gene) as tumor driver mutations. These three mutations, affecting cell cycle control and apoptosis, are functionally distinct from mutations that accumulated earlier, many of which are involved in inflammation/immunity or cell anchoring. These distinct functions of mutations at different stages may reflect the genetic interactions underlying tumor growth.     

Clinical and hereditary features of familial vitreous amyloidosis in chinese

Purpose:To investigate the clinical and hereditary features of a Chinese Han pedigree with familial vitreous amyloidosis.Methods:The hereditary features of familial traits were detected by drawing genealogy,and the clinical menifestations were observed.Results:This family with 4 generations of 32 family members had the characteristics of euchromosome dominant inheritance.The age of onset in heterozygotes was over 40 years old in male and over 55 in female.All affected individuals had curly hair.Among the 23 family members of the first 3 generations,7 had the final diagnosis.Four of the cases treated by vitrectomy was found to have open angle glaucoma during the follow-up.Conclusion:We reported a Chinese Han pedigree with familial vitreous amyloidosis which is a rare condition in Chinese and described the clinical and hereditary features.The genetic sequencing and animal model are undergoing.     

A review of family donor constructs: current research and future directions

This review addresses research on gamete donors, recipients, and offspring and demonstrates that the foci on all three within the triad are largely directed at disclosure or anonymity; and each in turn centers on the perceived importance of the genetic link. The importance attached to genetics has led some countries to review the ethics of anonymous gamete donation (e.g. New Zealand's 'open system' of information sharing) and has led other countries (Sweden, Austria, Victoria, Australia; the Netherlands, the UK) to change their laws allowing donor gamete offspring the right to obtain identifying information about their genetic parent. This review demonstrates that genealogical inconsistencies between and within members of the triad are common regardless of legislation. A discussion of future trends and concerns, relating to the use of gamete donation and the effects legislation is likely to have on the donor triads in the UK following 2005, is provided. The review also addresses the importance of testing theoretical models within future research, and argues this would lead to a better understanding of the underlying problems encountered at a psychosocial level, such as continued preference for anonymity in donors and denial in large numbers of users of the involvement of a donor in conception. Lack of disclosure effectively prevents true implementation of legislation; if a child is not informed, it is the result of donated gametes, it cannot take up the legally available option of finding out identifiable information about their genetic parent(s).     

Impact of a Cancer Registry-Based Genealogy Service to Support Clinical Genetics Services

In collaboration with the network of genetics clinics in Scotland, a brief questionnaire was designed to gather data prospectively about the impact of information arising from pedigree research provided by Scottish Cancer Registry personnel. Pedigree research in Scotland is facilitated by access to public records of births, deaths, marriages, and historic census returns up to 1901, and enables the construction of accurate and extensive family pedigrees encompassing generations beyond the detailed knowledge of the proband. Subject to existing confidentiality guidelines, linkage of these pedigrees to cancer registration records results in a more comprehensive family history including the age at diagnosis of any cancer, multiple primary cancers, and cancers unreported from death certificates. Of 454 requests for pedigree research completed between 1 April 2002 and 31 March 2003, questionnaires were returned for 425 (94%). The information fed back to genetics clinics led to changes in family history, risk categorisation, and management in 41%, 30%, and 23% of cases, respectively. Management advice altered in both directions, that is, to institute active follow-up and surveillance of clinic attendees and their relatives where none was previously envisaged, and viceversa. The interests of current and future generations of patients concerned about their familial risk of cancer will be served by measures which enable cancer registries to collect data that are as accurate and complete as possible.     

Caring as a slave morality: Nietzschean themes in nursing ethics

BACKGROUND: Sceptical arguments about 'caring' can be divided into three categories. First, it is suggested that, while caring is no doubt an admirable thing in itself, it is just one ideal among others. Secondly, it is claimed that caring is not really a virtue at all, and that it should be regarded as more of a vice, because it promotes favouritism, injustice, and self-deception. Thirdly, there is a worry that caring is not politically realistic, and that its advocates underestimate the powerful organizational and social structures which conspire to subvert nursing. AIM: This paper outlines a fourth, and more radical, type of scepticism, which explains why caring is subject to these drawbacks. In doing so, it considers the relation between caring, phenomenology and holism in nursing discourse, and the way in which all three fit together to form the 'caring paradigm'. METHODS: The paper adopts a genealogical approach, borrowed directly from Nietzsche's Genealogy of Morality. That book argues that the values associated with caring are the expression of a profound resentment, harboured by the slaves (weak, powerless, timorous) against the nobles (strong, powerful, self-confident). Caring represents an inversion, a sort of 'fantasy revenge', in which the nobles can be portrayed as 'evil', while the slaves portray their own weakness as 'good'. Taking its cue from Nietzsche, the paper shows that the Genealogy narrative can be transposed into a modern health care context, with nurses as the 'slaves' and the medical profession as the 'nobles'. CONCLUSIONS: The ideology of caring is, in the Genealogy's terms, a slave morality. It represents an attack on the 'medical-scientific model', motivated by resentment, and designed to establish nursing's superiority. Its effects have been debilitating, and it has prevented nursing from becoming a 'noble' (that is, a properly scientific) discipline.