Abstract: Segmental copy-number variations (CNVs) in the human genome are associated with developmental disorders and susceptibility to diseases. More importantly, CNVs may represent a major genetic component of our phenotypic diversity. In this study, using a whole-genome array comparative genomic hybridization assay, we identified 3,654 autosomal segmental CNVs, 800 of which appeared at a frequency of at least 3%. Of these frequent CNVs, 77% are novel. In the 95 individuals analyzed, the two most diverse genomes differed by at least 9 Mb in size or varied by at least 266 loci in content. Approximately 68% of the 800 polymorphic regions overlap with genes, which may reflect human diversity in senses (smell, hearing, taste, and sight), rhesus phenotype, metabolism, and disease susceptibility. Intriguingly, 14 polymorphic regions harbor 21 of the known human microRNAs, raising the possibility of the contribution of microRNAs to phenotypic diversity in humans. This in-depth survey of CNVs across the human genome provides a valuable baseline for studies involving human genetics.

Abstract: The concept of genetic balance traces back to the early days of genetics. Additions or subtractions of single chromosomes to the karyotype (aneuploidy) produced greater impacts on the phenotype than whole-genome changes (ploidy). Studies on changes in gene expression in aneuploid and ploidy series

Abstract: The field of human genetics of infectious diseases defines the genes and alleles rendering individuals (clinical genetics) and populations (epidemiological genetics) vulnerable to infection, and studies those selected by previous infections (evolutionary genetics). These disciplines—clinical, epidemiological and evolutionary genetics—delineate the redundant and nonredundant functions of host defense genes for past and present survival in natura—in natural ecosystems governed by natural selection. These disciplines, in other words, assess the ecologically relevant and evolutionarily selected roles of human genes and alleles in protective immunity to diverse and evolving microorganisms. The genetic dissection of human immunity to infection in natura provides unique immunological insight, making it an indispensable complement to experimental immunology in vitro and in vivo in plants and animals.

Abstract: Since the early 1950s, the dominant paradigm in the human genetics of infectious diseases postulates that rare monogenic immunodeficiencies confer vulnerability to multiple infectious diseases (one gene, multiple infections), whereas common infections are associated with the polygenic inheritance of multiple susceptibility genes (one infection, multiple genes). Recent studies, since 1996 in particular, have challenged this view. A newly recognised group of primary immunodeficiencies predisposing the individual to a principal or single type of infection is emerging. In parallel, several common infections have been shown to reflect the inheritance of one major susceptibility gene, at least in some populations. This novel causal relationship (one gene, one infection) blurs the distinction between patient-based Mendelian genetics and population-based complex genetics, and provides a unified conceptual frame for exploring the molecular genetic basis of infectious diseases in humans.

Abstract: We review three approaches to the genetic analysis of the biology and pathobiology of human aging. The first and so far the best-developed is the search for the biochemical genetic basis of varying susceptibilities to major geriatric disorders. These include a range of progeroid syndromes. Collectively, they tell us much about the genetics of health span. Given that the major risk factor for virtually all geriatric disorders is biological aging, they may also serve as markers for the study of intrinsic biological aging. The second approach seeks to identify allelic contributions to exceptionally long life spans. While linkage to a locus on Chromosome 4 has not been confirmed, association studies have revealed a number of significant polymorphisms that impact upon late-life diseases and life span. The third approach remains theoretical. It would require longitudinal studies of large numbers of middle-aged sib-pairs who are extremely discordant or concordant for their rates of decline in various physiological functions. We can conclude that there are great opportunities for research on the genetics of human aging, particularly given the huge fund of information on human biology and pathobiology, and the rapidly developing knowledge of the human genome.

Abstract: It is widely assumed that human noncoding sequences comprise a substantial reservoir for functional variants impacting gene regulation and other chromosomal processes. Evolutionarily conserved noncoding sequences (CNSs) in the human genome have attracted considerable attention for their potential to simplify the search for functional elements and phenotypically important human alleles. A major outstanding question is whether functionally significant human noncoding variation is concentrated in CNSs or distributed more broadly across the genome. Here, we combine wholegenome sequence data from four nonhuman species (chimp, dog, mouse, and rat) with recently available comprehensive human polymorphism data to analyze selection at single-nucleotide resolution. We show that a substantial fraction of active purifying selection in human noncoding sequences occurs outside of CNSs and is diffusely distributed across the genome. This finding suggests the existence of a large complement of human noncoding variants that may impact gene expression and phenotypic traits, the majority of which will escape detection with current approaches to genome analysis.

Abstract: A report on the Cancer Research UK London Research Institute Special Conference 'Signal Transduction', London, UK, 14-16 May 2007.

Abstract: Mutations in the FBN1 gene are the major cause of Marfan syndrome (MFS), an autosomal dominant connective tissue disorder, which displays variable manifestations in the cardiovascular, ocular, and skeletal systems. Current molecular genetic testing of FBN1 may miss mutations in the promoter region or in other noncoding sequences as well as partial or complete gene deletions and duplications. In this study, we tested for copy number variations by successively applying multiplex ligation-dependent probe amplification (MLPA) and the Affymetrix Human Mapping 500 K Array Set, which contains probes for approximately 500,000 single-nucleotide polymorphisms (SNPs) across the genome. By analyzing genomic DNA of 101 unrelated individuals with MFS or related phenotypes in whom standard genetic testing detected no mutation, we identified FBN1 deletions in two patients with MFS. Our high-resolution approach narrowed down the deletion breakpoints. Subsequent sequencing of the junctional fragments revealed the deletion sizes of 26,887 and 302,580 bp, respectively. Surprisingly, both deletions affect the putative regulatory and promoter region of the FBN1 gene, strongly indicating that they abolish transcription of the deleted allele. This expectation of complete loss of function of one allele, i.e. true haploinsufficiency, was confirmed by transcript analyses. Our findings not only emphasize the importance of screening for large genomic rearrangements in comprehensive genetic testing of FBN1 but, importantly, also extend the molecular etiology of MFS by providing hitherto unreported evidence that true haploinsufficiency is sufficient to cause MFS.

Abstract: The human growth hormone gene (GH1) and the insulin-like growth factor 1 and 2 genes (IGF1 and IGF2) encode the central elements of a key pathway influencing growth in humans. This “growth pathway” also includes transcription factors, agonists, antagonists, receptors, binding proteins, and endocrine factors that constitute an intrincate network of feedback loops. GH1 is evolutionarily coupled with other genes in linkage disequilibrium in 17q24.2, and the same applies to IGF2 in 11p15.5. In contrast, IGF1 in 12q22-24.1 is not in strong linkage disequilibrium with neighbouring genes. Knowledge of the functional architecture of these regions is important for the understanding of the combined evolution and function of GH1, IGF2 and IGF1 in relation to complex diseases. A number of mutations accounting for rare Mendelian disorders have been described in GH-IGF elements. The constellation of genes in this key pathway contains potential candidates in a number of complex diseases, including growth disorders, metabolic syndrome, diabetes (notably IGF2BP2) cardiovascular disease, and central nervous system diseases, and in longevity, aging and cancer. We review these genes and their associations with disease phenotypes, with special attention to metabolic risk traits.

Abstract: Outcome measurement in clinical genetics is challenging. Outcome attributes used currently have been developed by service providers or adapted from measures used in other areas of healthcare. Many of the ‘patients’ in clinical genetics are healthy but at risk of developing or transmitting a condition. Usually no pharmacological or surgical treatment is offered, although information-giving is an objective of most consultations. We argue that services should be evaluated on the basis of how well they alleviate the effects of disease, from a patient perspective. This paper describes a qualitative study using seven focus groups with health professionals, patients and patient representatives. Social and emotional effects of genetics diseases were identified. Some differences emerged between the effects identified by health professionals and those identified by patients. These findings will be used to inform the evaluation of existing outcome measures and develop robust measures of outcome for clinical genetics services.

Abstract: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The tumors characteristically harbor KIT or PDGFRA mutations, and mutant tumors respond to imatinib mesylate (Glivec™). Chromosomal imbalances resulting in altered gene dosage are known to have a role in the molecular pathogenesis of these tumors, but the target genes remain to be identified. The present study aimed to identify some of these genes. In total, 35 GIST samples were screened for chromosomal imbalances by array‐based comparative genomic hybridization. A cDNA array was used to define the minimal common overlapping areas of DNA copy number change. Eight confirmative, replicate hybridizations were performed using an oligonucleotide array. The most recurrent copy number losses were localized to 14q, 22q, and 1p. Gains were less common with 8q being the most recurrent. Two recurrent deleted regions of 14q were 14q11.2 harboring the PARP2, APEX1, and NDRG2 genes and 14q32.33 harboring SIVA. Additional target candidates were NF2 at chromosome 22, CDKN2A/2B at 9p, and ENO1 at 1p for copy number losses, and MYC at 8q for copy number gains. Array CGH proved to be an effective tool for the identification of chromosome regions involved in the development and progression of GISTs. © 2007 Wiley‐Liss, Inc.

Abstract: Our molecular understanding of growth hormone-induced signal transduction has improved significantly over the past decades. At the same time, human population genetics and the analysis of genetically engineered animals have led to the discovery of genes that control specific aspects of the overall growth process. Although, currently, growth disorders are still diagnosed and treated on empirical bases, it might soon be possible to stratify patients predominantly by genetic defect, with treatment based on our molecular understanding of the role of the affected gene in the disease.

Abstract: The small, maternally inherited mitochondrial DNA (mtDNA) has turned out to be a hotbed of pathogenic mutations: 15 years into the era of 'mitochondrial medicine', over 150 pathogenic point mutations and countless rearrangements have been associated with a variety of multisystemic or tissue-specific human diseases. MtDNA-related disorders can be divided into two major groups: those due to mutations in genes affecting mitochondrial protein synthesis in toto and those due to mutations in specific protein-coding genes. Here we review the mitochondrial genetics and the clinical features of the mtDNA-related diseases.

Abstract: Kinetochores are protein complexes established at eukaryotic centromeres and responsible for the correct chromosome segregation during nuclear divisions. Kinetochore formation is initiated by substitution of histone H3 by CENH3 within some but not all centromeric nucleosomes. Correct timing and targeting of this process are essential for centromere function, but are not well understood. In this paper, we point out that CENH3 loading in plants occurs before mitotic sister centromere separation, while in animals, it was recently shown to occur after sister centromere separation. Additionally, monocentric chromosomes of higher plants display distinct sister kinetochores immediately after loading of CENH3 during late G2. Although the reason for the different timing of CENH3 deposition is not yet clear, it indicates different mechanisms of regulation for CENH3 loading between animals and plants.

Abstract: Background One of the causes of Parkinson's disease is mutations in the PARK2 gene. Deletions and duplications of single exons or exon groups account for a large proportion of the gene mutations. Direct detection of these mutations can be used for the diagnosis of Parkinson's disease.

Abstract: A report on the Keystone Symposium 'Epigenetics: Regulation of Chromatin Structure in Development and Disease', Breckenridge, USA, 11-16 April 2007.

Abstract: Mitochondrial diseases are a group of disorders due to a mitochondrial respiratory chain deficiency. They may depend on mitochondrial genome (mtDNA-related disorders) as well as on a nuclear genome defect (nDNA-related disorders). mtDNA-related disorders encompass an increasing number of clinical pictures associated with more than 250 different provisional or confirmed pathogenic changes in mtDNA. Although some clinical syndromes are nosologically defined, most of the cases present with polymorphous phenotypes ranging from pure myopathy to multi-system involvement. Complexity of mitochondrial genetics is in part responsible for the extreme clinical intra- and inter-familial heterogeneity of this group of diseases. In this review, we briefly report an updated classification and overview the main clinical pictures of this class of diseases.

Abstract: An extensive range of molecular defects have been identified in the human mitochondrial genome (mtDNA), causing a range of clinical phenotypes characterized by mitochondrial respiratory chain dysfunction Sadly, given the complexities of mitochondrial genetics, there are no available cures for mtDNA disorders In this review, we consider experimental, genetic-based strategies that have been or are being explored towards developing treatments, focussing on two specific areas which we are actively pursuing—assessing the benefit of exercise training for patients with mtDNA defects, and the prevention of mtDNA disease transmission

Abstract: Pathogenic mutations in BRCA1 and BRCA2 have been reported in about 55–59% of breast and ovarian cancer (HBOC) families of French Canadian descent, where about 70% of families with more than two cases of ovarian cancer were mutation-positive. Given that specific subtypes of ovarian cancer are associated with mutation-positive families, we reviewed the features of 54 HBOC families of French Canadian descent that had histopathologically confirmed cases of invasive ovarian cancer where the BRCA1 and BRCA2 mutation status is known, and 27 families harbored germline mutations. The number of cases and ages of diagnosis of either breast cancers or ovarian cancers did not differ significantly in comparisons of mutation-positive and mutation-negative groups. However, the distribution of histopathological subtypes for the 79 cases of invasive epithelial cancer from the 54 HBOC families differed when grouped according to familial mutation status. The mutation-negative group had significantly more cases of the mucinous subtype of ovarian cancer when compared with the BRCA1 (P = 0.005) and BRCA2 (P = 0.017) mutation-positive groups. The presence of a mucinous subtype ovarian cancer in multiple young age of onset breast and/or ovarian mutation-negative HBOC cancer families warrants further investigation, as these families appear to exhibit features most consistent with BRCA1 and BRCA2 carrier status.

Abstract: Genome-wide association studies provide a new and powerful approach to investigate the effect of inherited genetic variation on the risk of human disease. These studies rely on high throughput DNA microarray technology to genotype hundreds of thousands of genetic variants across the human genome. The first genome-wide association studies have identified previously unknown genetic risk factors that influence a range of diseases, including prostate cancer, breast cancer, myocardial infarction, age-related macular degeneration, diabetes, Crohn's disease and obesity. Many more studies are currently underway, including a number that will focus on other cancers (e.g., colorectal). Here we discuss the major issues involved in conducting genome-wide association studies and how these studies can be used to examine cancer phenotypes.

Abstract: Background Ongoing advances in cancer genetics lead to new opportunities for early disease detection, predictive genetic testing and potential interventions. Limited information exists on patient preferences concerning recontact to provide updated information. We evaluated colon cancer genetics patient preferences concerning recontact about advances in medical genetics.

Abstract: Diseases such as congenital birth defects, myocardial infarction, cancer, mental illness, diabetes, and Alzheimer disease cause morbidity and premature mortality in nearly two of every three individuals during their lifetimes (Table 8-1). Many of these diseases “run in families”—they seem to recur in the relatives of affected individuals more frequently than in the general population. And yet their inheritance generally does not follow one of the mendelian patterns seen in the single-gene disorders (described in Chapter 7). Instead, they are thought to result from complex interactions between a number of genetic and environmental factors and therefore are said to follow a multifactorial (or complex) inheritance pattern. The familial clustering can be explained by recognizing that family members share a greater proportion of their genetic information and environmental exposures than do individuals chosen at random in the population. Thus, the relatives of an affected individual are more likely to experience the same gene-gene and gene-environment interactions that led to disease in the proband in the fi rst place than are individuals who are unrelated to the proband. The multifactorial inheritance pattern that results represents an interaction between the collective effect of the genotype at one or, more commonly, multiple loci (polygenic or multigenic effects) either to raise or to lower susceptibility to disease, combined with a variety of environmental exposures that may trigger, accelerate, exacerbate, or protect against the disease process. The gene-gene interactions in polygenic inheritance may be simply additive or much more complicated. For example, there may be synergistic amplifi cation of susceptibility by the genotypes at multiple loci or dampening of the effect of genotype at one locus by the genotypes at other loci. Gene-environment interactions, including systematic exposures or chance encounters with environmental factors in one’s surroundings, add even more complexity to individual disease risk and the pattern of disease inheritance. In this chapter, we fi rst address the question of how we determine that genes predispose to common diseases and, therefore, that these diseases are, at least in part, “genetic.” We describe how studies of familial aggregation, twin studies, and estimates of heritability are used by geneticists to quantify the relative contributions of genes and environment to diseases and clinically important physiological measures with complex inheritance. Second, we illustrate the general concept of gene-gene interaction, starting with one of the simplest examples, one in which modifi er genes affect the occurrence or severity of a mendelian disorder. We then give a few examples of more complicated multifactorial diseases in which knowledge of the alleles and loci that confer disease susceptibility is leading to an increased understanding of the mechanisms by which these alleles interact with each other or the environment to cause disease. Unfortunately, we do not understand the underlying mechanisms of the gene-gene and geneenvironment interactions for the majority of complex disorders. Geneticists must therefore continue to rely on empirically derived risk fi gures to give our patients and their relatives some answers to basic questions about disease risk and approaches to reducing that risk. We provide such risk fi gures here but expect that, with

Abstract: Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA), phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS.

Abstract: Sirs, About 3% of cases of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder, are due to mutations in the copper–zinc superoxide dismutase gene, SOD1. We have analyzed the variation in age at onset (AAO) in pedigrees with SOD1 mutations that are both common and have a strong founder effect, A4V and D90A [1–3]. Besides differences in phenotype and survival time, these mutations are each genetically homogeneous with a wide range of AAO (20–94 years). The variation in disease onset among individuals affected by the same SOD1 mutation and within members of the same family may, therefore, be due to factors other than mutation site in the SOD1 gene. We estimated the heritability of AAO within a variance components framework using two different programs, Mx and QTDT (“Supplementary methods”). We modeled AAO for affected individuals as the age of first-reported ALS symptoms or for unaffected individuals who carried the at-risk genotype (homozygous in the recessive D90A families and heterozygous in the dominant A4V families) as the age at last examination. In affected individuals, AAO was, therefore, less than or equal to the age at examination, and in unaffected individuals, AAO was greater than the age at examination [4]. AAO was, thus, a right-truncated quantitative trait in affected individuals and a left-truncated quantitative trait in those carrying the at-risk genotype. We analysed 55 families, Neurogenetics (2007) 8:235–236 DOI 10.1007/s10048-007-0092-2

Abstract: Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by absence of sexual maturation in the setting of low sex steroids and low/normal gonadotropins. Despite its rarity, considerable genetic heterogeneity and phenotypic variability exists in this disorder. Loss of function mutations in a G protein coupled receptor, GPR54, have been shown to cause IHH. Although mutations in GPR54 are not a common cause of this condition, patients bearing mutations are critical to explore genotype-phenotype correlations and gene function. In this review, we will examine the human genetics studies of GPR54, the phenotypic implications of mutations in this gene, and the emerging roles of the kisspeptin/GPR54 pathway.

Abstract: PURPOSE OF REVIEW The identification of regulatory polymorphisms has become a key problem in human genetics. In the past few years there has been a conceptual change in the way in which regulatory single-nucleotide polymorphisms are studied. We revise the new approaches and discuss how gene expression studies can contribute to a better knowledge of the genetics of common diseases. RECENT FINDINGS New techniques for the association of single-nucleotide polymorphisms with changes in gene expression have been recently developed. This, together with a more comprehensive use of the old in-vitro methods, has produced a great amount of genetic information. When added to current databases, it will help to design better tools for the detection of regulatory single-nucleotide polymorphisms. SUMMARY The identification of functional regulatory single-nucleotide polymorphisms cannot be done by the simple inspection of DNA sequence. In-vivo techniques, based on primer-extension, and the more recently developed 'haploChIP' allow the association of gene variants to changes in gene expression. Gene expression analysis by conventional in-vitro techniques is the only way to identify the functional consequences of regulatory single-nucleotide polymorphisms. The amount of information produced in the last few years will help to refine the tools for the future analysis of regulatory gene variants.