The MC1R and human pigmentation and skin cancer

In 1993, Roger Cone and co-workers showed that a range of murine coat colour mutations were due to mutations of the MC1R gene (Robbins et al., 1993). In the mouse (and subsequently a range of other mammals) loss of function recessive mutations at mclr resulted in a decrease in the ratio of eumelanin to pheomelanin, leading to a yellow (or red) coat. By contrast, dominant gain of function mutations lead to an increase in this ratio, leading to dark brown-black hair (Robbins et al., 1993). Why a...

Dirk Jan Kleinjan

The completion of the human genome project has heralded a new era in biology. Undoubtedly, knowledge of the genetic blueprint will expedite the search for genes responsible for specific medical disorders, simplify the search for mammalian homologues of crucial genes in other biological systems and assist in the prediction of the variety of gene products found in each cell. It can also assist in determining the small but potentially significant genetic variations between individuals. However,...

Investigations of specific cancers Bowel cancer

The descriptive epidemiology of bowel cancer indicates wide variation in cancer incidence rates across the world with the highest rates in Western Europe, USA, Canada, Australia and New Zealand (Potter and Hunter, 2002). The lowest rates are in parts of South Africa and Southern Asia. Rates have varied marginally by time across most countries but the most notable change has been in Japan where the incidence rate have risen from being among the lowest to among the highest in a couple of...

Malaria

Malaria provides the classic example of an infectious disease exerting an evolutionary pressure on humans so that protective mutations in genes are maintained in the populations who live in malaria endemic areas. Once the close geographical correlation of the prevalences of malaria and red blood cell disorders (hemoglobinopathies) was noted, Haldane proposed, in the late 1940s, that they might be protective against severe malaria (Haldane, 1949). Only a few years later Allison published the...

Monogenic disorders causing impaired reverse cholesterol transport

Low HDL cholesterol is a common finding in patients with premature CHD and usually precedes clinically apparent CHD (Goldbourt et al., 1997). Low HDL concentrations are most frequently associated with the components of the metabolic syndrome X and are rarely due to single-gene disorders (Durrington, 2003). The rare Tangier disease, characterized by very low or even immeasurable high density lipoprotein (HDL) cholesterol concentrations and reduced LDL cholesteryl ester, is due to mutations in...

Acne acne vulgaris OMIM 604324

Acne is an inflammatory dermatosis, the genetics of which have not been well studied. Acne is characterized by the development of inflammatory papules, comedones and pustules, leading on to possible disfiguring scarring. At a minimal level of severity, acne is ubiquitous in adolescence, and only a minority of cases will develop scarring or have a clinical course running into the second quarter of life. Three etiological factors are known sebum excretion from sebaceous glands, infection, and...

A thalassemia due to mutations in a transacting factor

Alpha thalassemia may rarely occur in association with developmental abnormalities including severe mental retardation, facial dysmorphism and urogenital abnormalities in an X-linked syndrome (ATRX) (Gibbons et al., 1995). The ATRX disease gene encodes a chromatin remodeling factor of the SWI SNF family that forms part of a large complex with a well-defined translocase activity. Although mutations in the ATRX gene clearly cause a thalassemia, the precise mechanism underlying this is currently...

Spatiotemporal patterns of common skin diseases

Given the paucity or absence of epidemiological data for most skin diseases, small changes in disease incidence are unlikely to be noticed. Clinical impressions of change in incidence are also confounded by the general increase in provision of healthcare in most developed countries over the last century, leading to a reduced threshold for visiting a physician. In addition, there are organizational differences between countries in what disorders fall within dermatology. For instance, in North...

Genomewide LD linkage disequilibrium patterning

LD, the non-random association of alleles at sites, is a critical factor in the mapping of genes affecting complex disease (see Chapters 3, 4). LD is affected by both population factors such as demography and selection, and by genetic factors such as recombination and mutation rates. In discussing the forces that shape LD, it is useful to distinguish those that influence patterning across the entire genome (e.g. a population bottleneck), from those that have more localized effects (e.g....

MYH protein function and interactions

Studies into the function of the BER proteins have been fuelled by its newly identified role in colorectal neoplasia (Cheadle and Sampson, 2003). The role of BER in removing oxidative damage is complex and there are several proteins employed to remove the damaged nucleotide. Studies of MYH have implicated it in the role of long patch BER (Parker et al., 2001) and in replication coupled repair (Boldogh et al., 2001). However, MYH function is generally implied from its E.coli homolog, MutY, which...

Allelic heterogeneity at Mendelian loci

The loci that underlie Mendelian traits often exhibit extensive allelic heterogeneity (Terwilliger and Weiss, 1998 Estivill et al., 1997). That is, there are often many different independent mutations at a single locus that cause disease. We now describe a simple population genetic model to understand allelic heterogeneity at such loci, and then briefly describe the extensions that have been used to predict what patterns of allelic heterogeneity are like at complex disease loci. Consider a...

Role of genetics in medical care of T2D

The value of obtaining a molecular diagnosis in individuals with early-onset forms of T2D was described earlier. The tight correlation between genotype and phenotype which characterizes MODY and other monogenic subtypes of diabetes and which has facilitated gene discovery efforts for these phenotypes, also means that genetic information gathered at these penetrant sites has the potential to deliver significant insights at the level of the individual, for example, in relation to the future risk...

Stephen P Robertson and Andrew OM Wilkie

An understanding of the complex processes that underlie the transition from zygote to newborn infant remains one of the major unsolved challenges in human biology. Failure of key steps in early embryogenesis leads to arrested development and embryonic wastage in a substantial proportion of conceptions (Wilcox et al., 1999). Interference with later developmental pathways which mediate the processes of morphogenesis and organogenesis can also lead to fetal demise but equally can produce a...

Apolipoprotein E APOE

The association of APOE with inherited susceptibility to AD was uncovered by the concurrence of three lines of investigation. Genetic linkage studies in pedigrees with predominantly late-onset, famili-ally aggregated AD provided suggestive evidence (z +2.5) for an AD susceptibility locus on chromosome 19q12-q13 near the APOE gene (Pericak-Vance et al., 1991). Second, analysis of proteins from the CSF which were capable of binding the Ab peptide revealed that one of the proteins was...

Conclusion

The consideration of legal and ethical issues in genetics and genomics serves to highlight a number of values which both the researcher and the clinician must bear in mind notions of sanctity of life, human dignity, autonomy, justice and solidarity, for example, are implicated at every turn, and are emphasized to varying degrees in the different contexts considered. As further evidenced in this, unfortunately brief, survey, there are a large number of issues that must be considered essential...

Measures of linkage disequilibrium

Briefly, the two most commonly used measures, ID 'I and r2 are introduced (for a more detailed discussion see chapters 3 and 5). If there are two loci, each with two alleles (A and a at the first locus and B and b at the second locus), and the frequencies of alleles A and B are pA and pB, respectively, and the frequency of alleles A and B together on the same chromosome is p , then the covariance between the loci is D pAB pApB, where pApB is the expected value of p in the absence of allelic...

The transcriptome and the proteome

An enormous amount of knowledge has been gained about genes since they were first discovered, including the fact that at the DNA level most genes in eukaryotes are split, i.e. they contain exons and introns (Berget et al., 1977 Chow et al., 1977) (Figure 1.1). The introns are removed from the RNA intermediate during gene expression in a process called RNA splicing. The split nature of many genes allows the opportunity to create multiple different messages through various mechanisms collectively...

Locus and allelic heterogeneity the good and the bad

The strategies for hunting genetic risk factors in common disease are mainly predicated on the common disease common variant hypothesis. Although we and others have challenged some of the assumptions inherent in this hypothesis (e.g. Wright and Hastie, 2001), there is no doubt that it applies in a number of cases. The most notable example is the increased risk of early-onset Alzheimer's disease for carriers of the apolipopro-tein E e4 allele and, conversely, the protective effect of the e2...

Van Buchems disease and sclerosteosis

Van Buchem's disease and sclerosteosis have very similar phenotypes with large increases in the amount of bone tissue Janssens and Van Hul, 2002 . Van Buchem's disease usually begins during puberty, with osteosclerosis of the skull, mandible, clavicles, ribs, and long bone diaphyses. In scle-rosteosis mainly the skull and mandible are affected, although osteosclerosis and hyperostosis can be more generalized. In both disorders optic atrophy and deafness can occur secondary to bone encroachment...

DNA methylation and cancer

In vertebrate somatic cells, epigenetic regulation of gene expression reinforces stable expression states at different loci. These ''expression states'' are associated with particular molecular signatures of DNA and chromatin modifications that are characteristic of active or repressed genes. The end result is that differentiated cells have a restricted transcriptome profile and a limited developmental potential. In cancer cells, this regulatory mechanism is altered such that the transcriptome...

DlWfl14 I I I H Hhh

Zinc Leucine FOX finger zipper domain motif Figure 31.2 Genomic structure and protein domains of FOXP2. Introns gt 50kb are indicated by . a single BAC clone that gave signals from both derivative chromosomes indicating it spanned the 7q31 breakpoint and may contain the disrupted SPCH1 gene. The gene disrupted by the translocation in CS, within the BAC clone, was characterized and designated FOXP2. FOXP2 was subsequently sequenced in KE family members and a G A nucleotide change causing an...

Familial British dementia FBD and familial encephalopathy with neuronal dementia with neuroserpin deposits

Recently, two very rare forms of inherited dementia Familial British dementia and familial encepha-lopathy with neuroserpin inclusion bodies FEN1B have been described which support the emerging concept that many of the inherited dementias are disorders of protein processing in which there is either intracellular or extracellular toxic accumulation of misfolded misprocessed proteins, a theme common to all of the diseases discussed here. Familial British dementia is characterized by spasticity,...

Prohormone convertase 1 deficiency

Further evidence for the role of the melanocortin system in the regulation of body weight in humans comes from the description of a 47-year-old woman with severe childhood obesity, abnormal glucose homeostasis, very low plasma insulin but elevated levels of proinsulin, hypogonadotropic hypogonadism and hypocortisolemia associated with elevated levels of POMC O'Rahilly et al., 1995 . This subject was found to be a compound heterozygote for mutations in prohormone conver-tase 1, which cleaves...

Rossi Naoumova Stuart A Cook Paul Cook and Timothy J Aitman

Coronary heart disease CHD is the single commonest cause of death in the developed world. One in four men and one in six women die from CHD. In the UK, around 15 of these deaths occur under the age of 65, and 35 under the age of 75 www.heartstats.org . CHD frequency varies between populations, with the highest age-adjusted rates of 600-1000 deaths per 100 000 found in countries of the former Soviet Union and the lowest at around 60 per 100000 in Japan World Health Organization 2002, www.who.ch...

Acknowledgements

Supported by the Wellcome Trust, MRC, Defeating Deafness and EC. Anagnostopoulos, A.V. 2002 . A compendium of mouse knockouts with inner ear defects. Trends Genet., 18, 499. Bitner-Glindzicz, M. 2002 . Hereditary deafness and phenotyping in humans. Br Med Bull., 63, 73-94. Browning, G.G. and Gatehouse, S. 1992 . The prevalence of middle ear disease in the adult British population. Clin Otolaryngol, 17, 317-21. Bykhovskaya, Y. et al. 2000 . Candidate locus for a nuclear modifier gene for...

Monogenic genes as genetic risk factors in common disease

Mobogenic Sexy Video

One other potential benefit deriving from the study of single gene disorders is that it provides candidate genetic risk factors for common disease. Given the chequered history of association studies, which have often been underpowered, it is difficult to tell whether most of the claimed associations will stand the test of time. However, there are Figure 10.1 Mortality from familial hypercholesterolemia according to sex and time. Mortality was estimated among 250 persons with 0.5 probability of...

Monogenic hypercholesterolemias

Cetp Pcsk9

Important insights into CHD pathogenesis have come from the study of monogenic hypercholes-terolemias, and have led to the development of the most widely used class of lipid-lowering drugs, the HMG-CoA-reductase inhibitors statins . Among the many known risk factors for atherosclerosis, very high low density lipoprotein LDL cholesterol levels are probably unique in their ability to lead to the development of premature atherosclerosis in humans in the absence of other additional risk factors....

Research involving human subjects

HSR sits at the nexus of laboratory science and clinical practice. It is a necessary medico-scientific 18 See, for example, the issues surrounding the patenting of the ONCO mouse in Canada, in Zahl 2004 and Kondro 2002 . pursuit, in that it is key to translating the promise of biomedical research into improvements in clinical practice.19 It is widely accepted, however, that HSR's propriety depends on its ethical foundation i.e. the protection of the rights and well-being of participants and the...

Goals of complex disease trait mapping

The main aims of these studies are - 1 to understand physiological and pathological mechanisms and pathways leading to disease through the identification of genetic factors underlying these processes. It is hoped that the resulting new knowledge will lead to new treatments and disease prevention strategies. 2 to identify increased genetic susceptibility within individuals where this risk has been shown to be reversible and amenable to reduction. This includes genetic redefinition of disease...

Classic teratogens

The ingestion of certain substances has been associated with fetal wastage and birth abnormalities since antiquity. A large number of teratogens have been identified by association through epide-miological means. Some of the effects of these agents are organ specific, the well-described association of the anti-nausea drug thalidomide with a specific form of underdevelopment of the limbs termed phocomelia, being a widely cited example Smithells, 1973 Holmes, 2002 . A difficulty in assessing many...

Donncha Dunican Sari Pennings and Richard Meehan

The coding capacity of the human genome is smaller than originally expected it is predicted that we have 25000-40 000 genes, only twofold more than a simple organism such as the roundworm C. elegans Pennisi, 2003 . This modest increase in gene numbers is counterbalanced by enormous gains in the potential for complex interactions through alternative splicing, and in the regulatory intricacy of elements within and between genes in chromatin Bentley, 2004 Chapter 1 . Added to this complexity is an...