Founder Effect: A phenomenon that is observed when a small subgroup of a larger POPULATION establishes itself as a separate and isolated entity. The subgroup's GENE POOL carries only a fraction of the genetic diversity of the parental population resulting in an increased frequency of certain diseases in the subgroup, especially those diseases known to be autosomal recessive.Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the MAJOR HISTOCOMPATIBILITY COMPLEX.Pedigree: The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition.Jews: An ethnic group with historical ties to the land of ISRAEL and the religion of JUDAISM.Microsatellite Repeats: A variety of simple repeat sequences that are distributed throughout the GENOME. They are characterized by a short repeat unit of 2-8 basepairs that is repeated up to 100 times. They are also known as short tandem repeats (STRs).Africa, Northern: The geographical area of Africa comprising ALGERIA; EGYPT; LIBYA; MOROCCO; and TUNISIA. It includes also the vast deserts and oases of the Sahara. It is often referred to as North Africa, French-speaking Africa, or the Maghreb. (From Webster's New Geographical Dictionary, 1988, p856)Gypsies: Ethnic group originating in India and entering Europe in the 14th or 15th century.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Indians, Central American: Individual members of Central American ethnic groups with ancient historic ancestral origins in Asia. Mexican Indians are not included.Genetic Variation: Genotypic differences observed among individuals in a population.Genetics, Population: The discipline studying genetic composition of populations and effects of factors such as GENETIC SELECTION, population size, MUTATION, migration, and GENETIC DRIFT on the frequencies of various GENOTYPES and PHENOTYPES using a variety of GENETIC TECHNIQUES.National Socialism: The doctrines and policies of the Nazis or the National Social German Workers party, which ruled Germany under Adolf Hitler from 1933-1945. These doctrines and policies included racist nationalism, expansionism, and state control of the economy. (from Columbia Encyclopedia, 6th ed. and American Heritage College Dictionary, 3d ed.)DNA Mutational Analysis: Biochemical identification of mutational changes in a nucleotide sequence.Consanguinity: The magnitude of INBREEDING in humans.Gene Frequency: The proportion of one particular in the total of all ALLELES for one genetic locus in a breeding POPULATION.Geography: The science dealing with the earth and its life, especially the description of land, sea, and air and the distribution of plant and animal life, including humanity and human industries with reference to the mutual relations of these elements. (From Webster, 3d ed)Genes, Recessive: Genes that influence the PHENOTYPE only in the homozygous state.Newfoundland and Labrador: Province of Canada consisting of the island of Newfoundland and an area of Labrador. Its capital is St. John's.Keratoderma, Palmoplantar: Group of mostly hereditary disorders characterized by thickening of the palms and soles as a result of excessive keratin formation leading to hypertrophy of the stratum corneum (hyperkeratosis).Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone.Dermatitis, Exfoliative: The widespread involvement of the skin by a scaly, erythematous dermatitis occurring either as a secondary or reactive process to an underlying cutaneous disorder (e.g., atopic dermatitis, psoriasis, etc.), or as a primary or idiopathic disease. It is often associated with the loss of hair and nails, hyperkeratosis of the palms and soles, and pruritus. (From Dorland, 27th ed)Indians, South American: Individual members of South American ethnic groups with historic ancestral origins in Asia.Genetic Structures: The biological objects that contain genetic information and that are involved in transmitting genetically encoded traits from one organism to another.Alleles: Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product.Australasia: Australia, New Zealand and neighboring islands in the South Pacific Ocean. (Random House Unabridged Dictionary, 2d ed.)Genetic Drift: The fluctuation of the ALLELE FREQUENCY from one generation to the next.Nontherapeutic Human Experimentation: Human experimentation that is not intended to benefit the subjects on whom it is performed. Phase I drug studies (CLINICAL TRIALS, PHASE I AS TOPIC) and research involving healthy volunteers are examples of nontherapeutic human experimentation.Homozygote: An individual in which both alleles at a given locus are identical.Genotype: The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS.DNA, Mitochondrial: Double-stranded DNA of MITOCHONDRIA. In eukaryotes, the mitochondrial GENOME is circular and codes for ribosomal RNAs, transfer RNAs, and about 10 proteins.Gene Flow: The change in gene frequency in a population due to migration of gametes or individuals (ANIMAL MIGRATION) across population barriers. In contrast, in GENETIC DRIFT the cause of gene frequency changes are not a result of population or gamete movement.Heterozygote: An individual having different alleles at one or more loci regarding a specific character.Arabs: Members of a Semitic people inhabiting the Arabian peninsula or other countries of the Middle East and North Africa. The term may be used with reference to ancient, medieval, or modern ethnic or cultural groups. (From Random House Unabridged Dictionary, 2d ed)Chromosome Mapping: Any method used for determining the location of and relative distances between genes on a chromosome.Chromosomes, Human, Y: The human male sex chromosome, being the differential sex chromosome carried by half the male gametes and none of the female gametes in humans.Phylogeny: The relationships of groups of organisms as reflected by their genetic makeup.Phenotype: The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event.Genetic Linkage: The co-inheritance of two or more non-allelic GENES due to their being located more or less closely on the same CHROMOSOME.Genetic Testing: Detection of a MUTATION; GENOTYPE; KARYOTYPE; or specific ALLELES associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing.Tunisia: A country in northern Africa between ALGERIA and LIBYA. Its capital is Tunis.Genetic Heterogeneity: The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Penetrance: The percent frequency with which a dominant or homozygous recessive gene or gene combination manifests itself in the phenotype of the carriers. (From Glossary of Genetics, 5th ed)Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Polymorphism, Genetic: The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level.France: A country in western Europe bordered by the Atlantic Ocean, the English Channel, the Mediterranean Sea, and the countries of Belgium, Germany, Italy, Spain, Switzerland, the principalities of Andorra and Monaco, and by the duchy of Luxembourg. Its capital is Paris.Exons: The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.Chromosomes, Human, Pair 2: A specific pair of human chromosomes in group A (CHROMOSOMES, HUMAN, 1-3) of the human chromosome classification.Mediterranean Region: The MEDITERRANEAN SEA, the MEDITERRANEAN ISLANDS, and the countries bordering on the sea collectively.Introduced Species: Non-native organisms brought into a region, habitat, or ECOSYSTEM by human activity.Genes, BRCA1: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human CHROMOSOME 17 at locus 17q21. Mutations of this gene are associated with the formation of HEREDITARY BREAST AND OVARIAN CANCER SYNDROME. It encodes a large nuclear protein that is a component of DNA repair pathways.Models, Genetic: Theoretical representations that simulate the behavior or activity of genetic processes or phenomena. They include the use of mathematical equations, computers, and other electronic equipment.EuropeMutation, Missense: A mutation in which a codon is mutated to one directing the incorporation of a different amino acid. This substitution may result in an inactive or unstable product. (From A Dictionary of Genetics, King & Stansfield, 5th ed)Genetic Speciation: The splitting of an ancestral species into daughter species that coexist in time (King, Dictionary of Genetics, 6th ed). Causal factors may include geographic isolation, HABITAT geometry, migration, REPRODUCTIVE ISOLATION, random GENETIC DRIFT and MUTATION.Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair.Germ-Line Mutation: Any detectable and heritable alteration in the lineage of germ cells. Mutations in these cells (i.e., "generative" cells ancestral to the gametes) are transmitted to progeny while those in somatic cells are not.BRCA2 Protein: A large, nuclear protein, encoded by the BRCA2 gene (GENE, BRCA2). Mutations in this gene predispose humans to breast and ovarian cancer. The BRCA2 protein is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (from Genes Dev. 2000;14(11):1400-6)Polymorphism, Single-Stranded Conformational: Variation in a population's DNA sequence that is detected by determining alterations in the conformation of denatured DNA fragments. Denatured DNA fragments are allowed to renature under conditions that prevent the formation of double-stranded DNA and allow secondary structure to form in single stranded fragments. These fragments are then run through polyacrylamide gels to detect variations in the secondary structure that is manifested as an alteration in migration through the gels.Family Health: The health status of the family as a unit including the impact of the health of one member of the family on the family as a unit and on individual family members; also, the impact of family organization or disorganization on the health status of its members.Spinocerebellar Degenerations: A heterogenous group of degenerative syndromes marked by progressive cerebellar dysfunction either in isolation or combined with other neurologic manifestations. Sporadic and inherited subtypes occur. Inheritance patterns include autosomal dominant, autosomal recessive, and X-linked.Biological Evolution: The process of cumulative change over successive generations through which organisms acquire their distinguishing morphological and physiological characteristics.Age of Onset: The age, developmental stage, or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual.FinlandItalyFrameshift Mutation: A type of mutation in which a number of NUCLEOTIDES deleted from or inserted into a protein coding sequence is not divisible by three, thereby causing an alteration in the READING FRAMES of the entire coding sequence downstream of the mutation. These mutations may be induced by certain types of MUTAGENS or may occur spontaneously.Evolution, Molecular: The process of cumulative change at the level of DNA; RNA; and PROTEINS, over successive generations.Emigration and Immigration: The process of leaving one's country to establish residence in a foreign country.Spain: Parliamentary democracy located between France on the northeast and Portugual on the west and bordered by the Atlantic Ocean and the Mediterranean Sea.Population Dynamics: The pattern of any process, or the interrelationship of phenomena, which affects growth or change within a population.Population Density: Number of individuals in a population relative to space.Sequence Analysis, DNA: A multistage process that includes cloning, physical mapping, subcloning, determination of the DNA SEQUENCE, and information analysis.AfricaPolymorphism, Single Nucleotide: A single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population.Polymorphism, Restriction Fragment Length: Variation occurring within a species in the presence or length of DNA fragment generated by a specific endonuclease at a specific site in the genome. Such variations are generated by mutations that create or abolish recognition sites for these enzymes or change the length of the fragment.Codon, Nonsense: An amino acid-specifying codon that has been converted to a stop codon (CODON, TERMINATOR) by mutation. Its occurance is abnormal causing premature termination of protein translation and results in production of truncated and non-functional proteins. A nonsense mutation is one that converts an amino acid-specific codon to a stop codon.IsraelQuebec: A province of eastern Canada. Its capital is Quebec. The region belonged to France from 1627 to 1763 when it was lost to the British. The name is from the Algonquian quilibek meaning the place where waters narrow, referring to the gradually narrowing channel of the St. Lawrence or to the narrows of the river at Cape Diamond. (From Webster's New Geographical Dictionary, 1988, p993 & Room, Brewer's Dictionary of Names, 1992, p440)Genetic Predisposition to Disease: A latent susceptibility to disease at the genetic level, which may be activated under certain conditions.Selection, Genetic: Differential and non-random reproduction of different genotypes, operating to alter the gene frequencies within a population.North AmericaSequence Deletion: Deletion of sequences of nucleic acids from the genetic material of an individual.Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships.Genes, Dominant: Genes that influence the PHENOTYPE both in the homozygous and the heterozygous state.Family: A social group consisting of parents or parent substitutes and children.Syndrome: A characteristic symptom complex.Chromosomes, Human, Pair 11: A specific pair of GROUP C CHROMOSOMES of the human chromosome classification.
Pedigree chart: A pedigree chart is a diagram that shows the occurrence and appearance or phenotypes of a particular gene or organism and its ancestors from one generation to the next,pedigree chart Genealogy Glossary - About.com, a part of The New York Times Company.Jewish Community Council of Victoria: The Jewish Community Council of Victoria Inc (JCCV) is the peak representative body for Victorian Jewry, representing nearly 60 Jewish community organisations and over 52,000 Victorian Jews. The JCCV’s mission is to represent the Victorian Jewish community, the largest Jewish community in Australia, on all matters that affect its status, welfare and interests.Microsatellite: A microsatellite is a tract of repetitive DNA in which certain DNA motifs (ranging in length from 2–5 base pairs) are repeated, typically 5-50 times. Microsatellites occur at thousands of locations in the human genome and they are notable for their high mutation rate and high diversity in the population.List of rivers in Western Sahara: This is a list of rivers in Western Sahara. This list is arranged north to south by drainage basin, with respective tributaries indented under each larger stream's name.Silent mutation: Silent mutations are mutations in DNA that do not significantly alter the phenotype of the organism in which they occur. Silent mutations can occur in non-coding regions (outside of genes or within introns), or they may occur within exons.Kuna people: The Guna, also known as Kuna or Cuna, are an indigenous people of Panama and Colombia. The current preferred and legally recognized spelling is Guna.Genetic variation: right|thumbPanmixia: Panmixia (or panmixis) means random mating.King C and Stanfield W.Mass suicides in 1945 Nazi Germany: Mass suicides in 1945 Nazi Germany among civilians, government officials and military personnel alike occurred with unusual frequency during the final weeks of Nazi Germany and the end of World War II in Europe for numerous reasons. These include the influence of Nazi propaganda, reaction to the suicide of Adolf Hitler, loyalty to the tenets of the Nazi Party, the nation's impending defeat in war, the anticipated Allied occupation of Nazi Germany, and fears of harsh treatment at the hands of military personnel both from the Western armies and the Soviet army.Cousin couple: A cousin couple is a pair of cousins who are involved in a romantic or sexual relationship.Health geography: Health geography is the application of geographical information, perspectives, and methods to the study of health, disease, and health care.OpsismodysplasiaNewfoundland Margarine Company Limited: The Newfoundland Butter Company founded by Sir John Chalker Crosbie in 1925 was one of threeVolume four, p. 168, Encyclopedia of Newfoundland and Labrador, ISBN 0-9693422-1-7.Hypotrichosis–acro-osteolysis–onychogryphosis–palmoplantar keratoderma–periodontitis syndrome: Hypotrichosis–acro-osteolysis–onychogryphosis–palmoplantar keratoderma–periodontitis syndrome (also known as "HOPP syndrome") is a cutaneous condition characterized by a prominent palmoplantar keratoderma.Disequilibrium (medicine): Disequilibrium}}ErythrodermaLampreado: thumb | 250px | right | LampreadoGenetic structure: Genetic structure refers to any pattern in the genetic makeup of individuals within a population.Infinite alleles model: The infinite alleles model is a mathematical model for calculating genetic mutations. The Japanese geneticist Motoo Kimura and American geneticist James F.Extra (gum): Extra is a brand of sugarfree chewing gum produced by the Wrigley Company in North America, Europe, and some parts of Africa and Australasia.Microevolution: Microevolution is the change in allele frequencies that occur over time within a population.Microevolution: What is microevolution?ATC code V07: ==V07A All other non-therapeutic products==Haplogroup L0 (mtDNA)National Arab American Medical Association: United StatesChromosome regionsBranching order of bacterial phyla (Gupta, 2001): There are several models of the Branching order of bacterial phyla, one of these was proposed in 2001 by Gupta based on conserved indels or protein, termed "protein signatures", an alternative approach to molecular phylogeny. Some problematic exceptions and conflicts are present to these conserved indels, however, they are in agreement with several groupings of classes and phyla.Phenotype microarray: The phenotype microarray approach is a technology for high-throughput phenotyping of cells.Genetic linkage: Genetic linkage is the tendency of alleles that are located close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. Genes whose loci are nearer to each other are less likely to be separated onto different chromatids during chromosomal crossover, and are therefore said to be genetically linked.List of butterflies of Tunisia: This is a list of butterflies of Tunisia. About 84 species are known from Tunisia.Genetic heterogeneity: Genetic heterogeneity is a phenomenon in which a single phenotype or genetic disorder may be caused by any one of a multiple number of alleles or non-allele (locus) mutations.Turnpenny and Ellard, Emery's Elements of Medical Genetics, 13th Edition.Symmetry element: A symmetry element is a point of reference about which symmetry operations can take place. In particular, symmetry elements can be centers of inversion, axes of rotation and mirror planes.Coles PhillipsGene polymorphismBudic II of Brittany: Budic II (; or ; ), formerly known as Budick, was a king of Cornouaille in Brittany in the late 5th and early 6th centuries. He was the father of Hoel Mawr and is probably to be identified with the Emyr Llydaw ("Emperor of Brittany") and King Nentres who appear in Arthurian legend.Alternative splicing: Alternative splicing is a regulated process during gene expression that results in a single gene coding for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene.Natural Park of El FondoLists of invasive species: These are lists of invasive species by country or region. A species is regarded as invasive if it has been introduced by human action to a location, area, or region where it did not previously occur naturally (i.GA²LENMissense mutation: In genetics, a missense mutation (a type of nonsynonymous substitution) is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. Another type of nonsynonymous substitution is a nonsense mutation in which a codon is changed to a premature stop codon that results in truncation of the resulting protein.Point mutationGermline STAT 1 Mutation: Interferons induce the formation of two transcriptional activators: gamma-activating factor (GAF) and interferon-stimulated gamma factor 3 (ISGF3). A natural heterozygous germline STAT1 mutation associated with susceptibility to mycobacterial but not viral disease was found in two unrelated patients with unexplained mycobacterial disease.Single-strand conformation polymorphism: Single-strand conformation polymorphism (SSCP), or single-strand chain polymorphism, is defined as conformational difference of single-stranded nucleotide sequences of identical length as induced by differences in the sequences under certain experimental conditions. This property allows sequences to be distinguished by means of gel electrophoresis, which separates fragments according to their different conformations.Australia–Finland relations: Australia–Finland relations are foreign relations between the Australia and Finland. Diplomatic relations were established on 31 May 1949.Triangle of death (Italy): The triangle of death (Italian: Triangolo della morte) is an area in the Italian province of Campania comprising the municipalities of Acerra, Nola and Marigliano. The region has recently experienced increasing deaths caused by cancer and other diseases that exceeds the Italian national average.Frameshift mutation: A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels (insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet nature of gene expression by codons, the insertion or deletion can change the reading frame (the grouping of the codons), resulting in a completely different translation from the original.Molecular evolution: Molecular evolution is a change in the sequence composition of cellular molecules such as DNA, RNA, and proteins across generations. The field of molecular evolution uses principles of evolutionary biology and population genetics to explain patterns in these changes.List of countries that regulate the immigration of felons: This is a list of countries that regulate the immigration of felons.List of lighthouses in Spain: This is a list of lighthouses in Spain.Matrix population models: Population models are used in population ecology to model the dynamics of wildlife or human populations. Matrix population models are a specific type of population model that uses matrix algebra.Threshold host density: Threshold host density (NT), in the context of wildlife disease ecology, refers to the concentration of a population of a particular organism as it relates to disease. Specifically, the threshold host density (NT) of a species refers to the minimum concentration of individuals necessary to sustain a given disease within a population.DNA sequencer: A DNA sequencer is a scientific instrument used to automate the DNA sequencing process. Given a sample of DNA, a DNA sequencer is used to determine the order of the four bases: G (guanine), C (cytosine), A (adenine) and T (thymine).MIM Pan-African Malaria Conference 2009WGAViewer: WGAViewer is a bioinformatics software tool which is designed to visualize, annotate, and help interpret the results generated from a genome wide association study (GWAS). Alongside the P values of association, WGAViewer allows a researcher to visualize and consider other supporting evidence, such as the genomic context of the SNP, linkage disequilibrium (LD) with ungenotyped SNPs, gene expression database, and the evidence from other GWAS projects, when determining the potential importance of an individual SNP.Amplified fragment length polymorphismNonsense mutation: In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation where a single nucleotide is changed to cause substitution of a different amino acid.Tel Aviv Sourasky Medical Center: Tel Aviv Sourasky Medical Center (commonly referred to as Ichilov Hospital) is the main hospital serving Tel Aviv, Israel, and its metropolitan area. It is the third-largest hospital complex in the country.List of subjects related to the Quebec independence movement: This is a list of subjects related to the Quebec independence movement.Selection (relational algebra): In relational algebra, a selection (sometimes called a restriction to avoid confusion with SQL's use of SELECT) is a unary operation written asAmerican Medical Student AssociationThermal cyclerIridogoniodysgenesis, dominant type: Iridogoniodysgenesis, dominant type (type 1, IRID1) refers to a spectrum of diseases characterized by malformations of the irido-corneal angle of the anterior chamber of the eye. Iridogoniodysgenesis is the result of abnormal migration or terminal induction of neural crest cells.Malformative syndrome: A malformative syndrome (or malformation syndrome) is a recognizable pattern of congenital anomalies that are known or thought to be causally related (VIIth International Congress on Human Genetics).
(1/781) A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer.
The frequency, origin, and phenotypic expression of a germline MSH2 gene mutation previously identified in seven kindreds with hereditary non-polyposis cancer syndrome (HNPCC) was investigated. The mutation (A-->T at nt943+3) disrupts the 3' splice site of exon 5 leading to the deletion of this exon from MSH2 mRNA and represents the only frequent MSH2 mutation so far reported. Although this mutation was initially detected in four of 33 colorectal cancer families analysed from eastern England, more extensive analysis has reduced the frequency to four of 52 (8%) English HNPCC kindreds analysed. In contrast, the MSH2 mutation was identified in 10 of 20 (50%) separately identified colorectal families from Newfoundland. To investigate the origin of this mutation in colorectal cancer families from England (n=4), Newfoundland (n=10), and the United States (n=3), haplotype analysis using microsatellite markers linked to MSH2 was performed. Within the English and US families there was little evidence for a recent common origin of the MSH2 splice site mutation in most families. In contrast, a common haplotype was identified at the two flanking markers (CA5 and D2S288) in eight of the Newfoundland families. These findings suggested a founder effect within Newfoundland similar to that reported by others for two MLH1 mutations in Finnish HNPCC families. We calculated age related risks of all, colorectal, endometrial, and ovarian cancers in nt943+3 A-->T MSH2 mutation carriers (n=76) for all patients and for men and women separately. For both sexes combined, the penetrances at age 60 years for all cancers and for colorectal cancer were 0.86 and 0.57, respectively. The risk of colorectal cancer was significantly higher (p<0.01) in males than females (0.63 v 0.30 and 0.84 v 0.44 at ages 50 and 60 years, respectively). For females there was a high risk of endometrial cancer (0.5 at age 60 years) and premenopausal ovarian cancer (0.2 at 50 years). These intersex differences in colorectal cancer risks have implications for screening programmes and for attempts to identify colorectal cancer susceptibility modifiers. (+info)
(2/781) Analysis of spinocerebellar ataxia type 2 gene and haplotype analysis: (CCG)1-2 polymorphism and contribution to founder effect.
Spinocerebellar ataxia type 2 is a familial spinocerebellar ataxia with autosomal dominant inheritance. The gene responsible was recently cloned and this disorder was found to be the result of a CAG expansion in its open reading frame. We analysed 13 SCA2 patients in seven unrelated families in Gunma Prefecture, Japan. In four of the seven families, we detected CCG or CCGCCG interruptions in only the expanded alleles. Cosegregation of these polymorphisms with SCA2 patients was established within each family. Together with the results of haplotype analyses, we considered that at least two founders were present in our area and that these (CCG)1-2 polymorphisms may make analysis of founder effects easier. By sequencing analysis we found that although the number of the long CAG repeat varied in each subclone of expanded alleles, these polymorphisms did not change their configuration. This finding suggests that CCG or CCGCCG sequences are stable when surrounded by the long CAG repeat and a single CAG. Moreover, the presence of these polymorphisms may lead to miscounting the repeat size by conventional estimation using a size marker such as an M13 sequencing ladder. Therefore we should consider these polymorphisms and accurately determine the repeat size by sequencing. (+info)
(3/781) Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a clinically homogeneous form of early-onset familial spastic ataxia with prominent myelinated retinal nerve fibers. More than 300 patients have been identified, and most of their families originated in the Charlevoix-Saguenay region of northeastern Quebec, where the carrier prevalence has been estimated to be 1/22. Consistent with the hypothesis of a founder effect, we observed excess shared homozygosity at 13q11, among patients in a genomewide scan of 12 families. Analysis of 19 pedigrees demonstrated very tight linkage between the ARSACS locus and an intragenic polymorphism of the gamma-sarcoglycan (SGCG) gene, but genomic DNA sequence analysis of all eight exons of SGCG revealed no disease-causing mutation. On the basis of haplotypes composed of seven marker loci that spanned 11.1 cM, the most likely position of the ARSACS locus was 0.42 cM distal to the SGCG polymorphism. Two groups of ARSACS-associated haplotypes were identified: a large group that carries a common SGCG allele and a small group that carries a rare SGCG allele. The haplotype groups do not appear to be closely related. Therefore, although chromosomes within each haplotype group may harbor a single ARSACS mutation identical by descent, the two mutations could have independent origins. (+info)
(4/781) Ancestral Asian source(s) of new world Y-chromosome founder haplotypes.
Haplotypes constructed from Y-chromosome markers were used to trace the origins of Native Americans. Our sample consisted of 2,198 males from 60 global populations, including 19 Native American and 15 indigenous North Asian groups. A set of 12 biallelic polymorphisms gave rise to 14 unique Y-chromosome haplotypes that were unevenly distributed among the populations. Combining multiallelic variation at two Y-linked microsatellites (DYS19 and DXYS156Y) with the unique haplotypes results in a total of 95 combination haplotypes. Contra previous findings based on Y- chromosome data, our new results suggest the possibility of more than one Native American paternal founder haplotype. We postulate that, of the nine unique haplotypes found in Native Americans, haplotypes 1C and 1F are the best candidates for major New World founder haplotypes, whereas haplotypes 1B, 1I, and 1U may either be founder haplotypes and/or have arrived in the New World via recent admixture. Two of the other four haplotypes (YAP+ haplotypes 4 and 5) are probably present because of post-Columbian admixture, whereas haplotype 1G may have originated in the New World, and the Old World source of the final New World haplotype (1D) remains unresolved. The contrasting distribution patterns of the two major candidate founder haplotypes in Asia and the New World, as well as the results of a nested cladistic analysis, suggest the possibility of more than one paternal migration from the general region of Lake Baikal to the Americas. (+info)
(5/781) The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews.
Three founder mutations in the cancer-associated genes BRCA1 and BRCA2 occur frequently enough among Ashkenazi Jews to warrant consideration of genetic testing outside the setting of high-risk families with multiple cases of breast or ovarian cancer. We estimated the prevalence of these founder mutations in BRCA1 and BRCA2 in the general population of Ashkenazi Jews according to age at testing, personal cancer history, and family cancer history. We compared the results of anonymous genetic testing of blood samples obtained in a survey of >5,000 Jewish participants from the Washington, DC, area with personal and family cancer histories obtained from questionnaires completed by the participants. In all subgroups defined by age and cancer history, fewer mutations were found in this community sample than in clinical series studied to date. For example, 11 (10%) of 109 Jewish women who had been given a diagnosis of breast cancer in their forties carried one of the mutations. The most important predictor of mutation status was a previous diagnosis of breast or ovarian cancer. In men and in women never given a diagnosis of cancer, family history of breast cancer before age 50 years was the strongest predictor. As interest in genetic testing for BRCA1 and BRCA2 in the Jewish community broadens, community-based estimates such as these help guide those seeking and those offering such testing. Even with accurate estimates of the likelihood of carrying a mutation and the likelihood of developing cancer if a mutation is detected, the most vexing clinical problems remain. (+info)
(6/781) The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease.
In 40 western European patients with Stargardt disease (STGD), we found 19 novel mutations in the retina-specific ATP-binding cassette transporter (ABCR) gene, illustrating STGD's high allelic heterogeneity. One mutation, 2588G-->C, identified in 15 (37.5%) patients, shows linkage disequilibrium with a rare polymorphism (2828G-->A) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3' splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of two STGD patients with the 2588G-->C mutation shows that the resulting mutant ABCR proteins either lack Gly863 or contain the missense mutation Gly863Ala. We hypothesize that the 2588G-->C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This is supported in that the accompanying ABCR mutations in at least five of eight STGD patients are null (severe) and that a combination of two mild mutations has not been observed among 68 STGD patients. The 2588G-->C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, the cystic fibrosis conductance regulator gene mutation DeltaPhe508. Given an STGD incidence of 1/10,000, homozygosity for the 2588G-->C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype. (+info)
(7/781) Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt-Jakob disease.
Creutzfeldt-Jakob disease (CJD) belongs to a group of prion diseases that may be infectious, sporadic, or hereditary. The 200K point mutation in the PRNP gene is the most frequent cause of hereditary CJD, accounting for >70% of families with CJD worldwide. Prevalence of the 200K variant of familial CJD is especially high in Slovakia, Chile, and Italy, and among populations of Libyan and Tunisian Jews. To study ancestral origins of the 200K mutation-associated chromosomes, we selected microsatellite markers flanking the PRNP gene on chromosome 20p12-pter and an intragenic single-nucleotide polymorphism at the PRNP codon 129. Haplotypes were constructed for 62 CJD families originating from 11 world populations. The results show that Libyan, Tunisian, Italian, Chilean, and Spanish families share a major haplotype, suggesting that the 200K mutation may have originated from a single mutational event, perhaps in Spain, and spread to all these populations with Sephardic migrants expelled from Spain in the Middle Ages. Slovakian families and a family of Polish origin show another unique haplotype. The haplotypes in families from Germany, Sicily, Austria, and Japan are different from the Mediterranean or eastern European haplotypes. On the basis of this study, we conclude that founder effect and independent mutational events are responsible for the current geographic distribution of hereditary CJD associated with the 200K mutation. (+info)
(8/781) Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31.
Familial dysautonomia (FD) is an autosomal recessive disorder characterized by developmental arrest in the sensory and autonomic nervous systems and by Ashkenazi Jewish ancestry. We previously had mapped the defective gene (DYS) to an 11-cM segment of chromosome 9q31-33, flanked by D9S53 and D9S105. By using 11 new polymorphic loci, we now have narrowed the location of DYS to <0.5 cM between the markers 43B1GAGT and 157A3. Two markers in this interval, 164D1 and D9S1677, show no recombination with the disease. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, might represent independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated DYS carrier frequency of 1 in 32, and none of the four haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. It is now possible to provide accurate genetic testing both for families with FD and for carriers, on the basis of close flanking markers and the capacity to identify >98% of FD chromosomes by their haplotype. (+info)