Dissecting a population genome for targeted screening of disease mutations

Department of Molecular Medicine, National Public Health Institute, Biomedicum, 00250 Helsinki, Finland.
Human Molecular Genetics (Impact Factor: 6.68). 01/2002; 10(26):2961-72.
Source: PubMed

ABSTRACT Compared to mixed populations, population isolates such as Finland show distinct differences in the prevalence of disease mutations. However, little information exists of the differences on the prevalence of different disease alleles in regional populations with different history of multiple bottlenecks. We constructed a DNA-array and monitored the prevalence of 31 rare and common disease mutations underlying 27 clinical phenotypes in a large population-based study sample. Over 64 000 genotypes were assigned in 2151 samples from four geographical areas representing early and late settlement regions of Finland. Each sample was analyzed in duplicate and a total of 142 000 array-derived genotyping calls were made. On average one in three individuals was found to be a carrier of one of the 31 monitored mutations. This should remove fears of the stigmatizing effect of a carrier-screening program monitoring multiple diseases. Regional differences were found in the prevalence of mutations, providing molecular evidence for the deviating population histories of regional subisolates. The mutations introduced early into the population revealed relatively even distribution in different subregions. More recently introduced rare mutations showed local clustering of disease alleles, indicating the persistence of population subisolates and the effect of multiple bottlenecks in molding the population gene pool. Regional differences were observed also for common disease alleles. Such precise information of the carrier frequencies could form the basis for targeted genetic screens in this population. Our approach describes a general paradigm for large-scale carrier-screening programs also in other populations.

  • Source
    • "An example of genetic isolates is the Finnish disease heritage, a group in which about 30 AR diseases occur more frequently than in the general population . Each of the 30 diseases has a major founder mutation (Pastinen et al., 2001). Consanguinity is common in some ethnic groups such as Arab communities in the Middle East (El Mouzan, Al Salloum, Al Herbish, Qurachi, & Al Omar, 2008), yet low in many Western countries as it may carry a social stigma, causing patients to avoid sharing this information with their care providers (Mensink & Hand, 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Thousands of single gene, mitochondrial, and chromosomal disorders have been described in children. The purpose of this article is twofold. The first is to increase nurses' awareness of new developments in genetic disorders that are commonly seen in practice and taught in schools of nursing. The second is to illustrate important genetic concepts of relevance to nurses who care for infants, children, or adolescents. Organizing Construct: This article is organized into four sections: one that describes new developments in a well-known disorder, a second that discusses the process and potential outcomes of diagnosing a very rare disorder, and the third and fourth sections that describe select conditions caused by single gene mutations. Methods: Clinical expertise was paired with literature review to present evidence-based current information. Implications for nursing practice are highlighted throughout the article. Citations of publicly available evidence-based online resources are used so nurses can continue to use these in their practices. Findings: Diagnosis and treatment strategies for children with genetic disorders are rapidly changing. While it is impossible to stay current in all disorders, resources are available to help nurses provide evidence-based care to children with genetic disorders. Clinical Relevance: Nurses have an important role in the early identification of children with genetic disorders and in facilitating their access to appropriate services and resources. Nurses can also help families understand why genetic testing may be necessary and assure families are informed throughout the process.
    Journal of Nursing Scholarship 01/2013; DOI:10.1111/jnu.12003 · 1.77 Impact Factor
  • Source
    • "The mapping and characterization of genes still awaiting these procedures and the determination of major and minor mutations are mainly questions of time and workload. The microchip method offers technical possibilities for heterozygote screening in several Finnish disease genes either to a nationwide or regional extent (Pastinen et al. 2001). Testing procedures, however, involve striking ethical, informational, and other practical problems, and their benefits in general and in relation to the costs are not easy to judge. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This review of the Finnish Disease Heritage (FDH), a group of rare hereditary diseases that are overrepresented in Finland, includes the following topics: FDH characteristics, causes and background, primary theory, revis(it)ed theory, consanguineous marriages in Finland, internal migration of the 1500s, family series for further FDH studies, geography and population structure as a basis for FDH, geography of individual diseases, the structure of FDH families, family structure in individual diseases, Finnish gene mutations, linkage disequilibrium and haplotypes, age of gene mutations, frequencies of disease genes and carriers, and a short description of the possible future of FDH.
    Human Genetics 06/2003; 112(5-6):441-56. DOI:10.1007/s00439-002-0875-3 · 4.52 Impact Factor
  • Source
    • "The GRACILE mutation most probably represents a relatively new mutation, enriched in the restricted regional subisolates of eastern and central Finland . We have earlier demonstrated quite significant regional differences in our DNA array-based identification of the carriers of Finnish mutations, reflecting the effect of multiple population bottlenecks during the inhabitation of the country (Pastinen et al. 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death) syndrome is a recessively inherited lethal disease characterized by fetal growth retardation, lactic acidosis, aminoaciduria, cholestasis, and abnormalities in iron metabolism. We previously localized the causative gene to a 1.5-cM region on chromosome 2q33-37. In the present study, we report the molecular defect causing this metabolic disorder, by identifying a homozygous missense mutation that results in an S78G amino acid change in the BCS1L gene in Finnish patients with GRACILE syndrome, as well as five different mutations in three British infants. BCS1L, a mitochondrial inner-membrane protein, is a chaperone necessary for the assembly of mitochondrial respiratory chain complex III. Pulse-chase experiments performed in COS-1 cells indicated that the S78G amino acid change results in instability of the polypeptide, and yeast complementation studies revealed a functional defect in the mutated BCS1L protein. Four different mutations in the BCS1L gene have been reported elsewhere, in Turkish patients with a distinctly different phenotype. Interestingly, the British and Turkish patients had complex III deficiency, whereas in the Finnish patients with GRACILE syndrome complex III activity was within the normal range, implying that BCS1L has another cellular function that is uncharacterized but essential and is putatively involved in iron metabolism.
    The American Journal of Human Genetics 11/2002; 71(4):863-76. DOI:10.1086/342773 · 10.99 Impact Factor
Show more