Biomedical subjects

Michael Morley

Publications and source records attributed to Michael Morley.

7 recordsLinked to original sources

PubMed2007

Common genetic variants account for differences in gene expression among ethnic groups.

Variation in DNA sequence contributes to individual differences in quantitative traits, but in humans the specific sequence variants are known for very few traits. We characterized variation in gene expression in cells from individuals belonging to three major population groups. This quantitative phenotype differs significantly between European-derived and Asian-derived populations for 1,097 of 4,197 genes tested. For the phenotypes with the strongest evidence of cis determinants, most of the variation is due to allele frequency differences at cis-linked regulators. The results show that specific genetic variation among populations contributes appreciably to differences in gene expression phenotypes. Populations differ in prevalence of many complex genetic diseases, such as diabetes and cardiovascular disease. As some of these are probably influenced by the level of gene expression, our results suggest that allele frequency differences at regulatory polymorphisms also account for some population differences in prevalence of complex diseases.

Ethnicity↗

PubMed2005

Mapping determinants of human gene expression by regional and genome-wide association.

To study the genetic basis of natural variation in gene expression, we previously carried out genome-wide linkage analysis and mapped the determinants of approximately 1,000 expression phenotypes. In the present study, we carried out association analysis with dense sets of single-nucleotide polymorphism (SNP) markers from the International HapMap Project. For 374 phenotypes, the association study was performed with markers only from regions with strong linkage evidence; these regions all mapped close to the expressed gene. For a subset of 27 phenotypes, analysis of genome-wide association was performed with >770,000 markers. The association analysis with markers under the linkage peaks confirmed the linkage results and narrowed the candidate regulatory regions for many phenotypes with strong linkage evidence. The genome-wide association analysis yielded highly significant results that point to the same locations as the genome scans for about 50% of the phenotypes. For one candidate determinant, we carried out functional analyses and confirmed the variation in cis-acting regulatory activity. Our findings suggest that association studies with dense SNP maps will identify susceptibility loci or other determinants for some complex traits or diseases.

Alleles↗

PubMed2004

Genetic analysis of genome-wide variation in human gene expression.

Natural variation in gene expression is extensive in humans and other organisms, and variation in the baseline expression level of many genes has a heritable component. To localize the genetic determinants of these quantitative traits (expression phenotypes) in humans, we used microarrays to measure gene expression levels and performed genome-wide linkage analysis for expression levels of 3,554 genes in 14 large families. For approximately 1,000 expression phenotypes, there was significant evidence of linkage to specific chromosomal regions. Both cis- and trans-acting loci regulate variation in the expression levels of genes, although most act in trans. Many gene expression phenotypes are influenced by several genetic determinants. Furthermore, we found hotspots of transcriptional regulation where significant evidence of linkage for several expression phenotypes (up to 31) coincides, and expression levels of many genes that share the same regulatory region are significantly correlated. The combination of microarray techniques for phenotyping and linkage analysis for quantitative traits allows the genetic mapping of determinants that contribute to variation in human gene expression.

Alleles↗

PubMed2004

Method for manufacturing whole-genome microarrays by rolling circle amplification.

Comparative genomic hybridization (CGH) to metaphase chromosomes is a method for genome-wide detection of chromosomal aberrations in DNA samples. Recent advances in microarray technology have improved CGH by replacing metaphase chromosomes with a collection of mapped genomic clones placed on glass slides. However, it is quite expensive and labor-intensive to prepare DNA from the genomic clones for use in constructing genomic microarrays. Here we used strand-displacement rolling circle amplification (RCA) to manufacture whole-genome microarrays by using a collection of about 4,500 mapped RPCI-11 BAC clones that cover the human genome at approximately a 1-Mb resolution. These genomic microarrays detected all major chromosomal aberrations in cancer cells lines and in cell lines with aneuploidy. In this article, we discuss the advantages of using RCA for the manufacturing of large genomic microarrays.

Cell Line, Tumor↗

PubMed2004

Direct IBD mapping: identical-by-descent mapping without genotyping.

Direct identical-by-descent (IBD) mapping is a technique, that combines genomic mismatch scanning (GMS) and DNA microarray technology, for mapping regions shared IBD between two individuals without locus-by-locus genotyping or sequencing. The lack of reagents has limited its widespread application. In particular, two key reagents have been limiting, 1). mismatch repair proteins MutS, L and H, and 2). genomic microarrays for identifying the genomic locations of the GMS-selected IBD fragments. Here, we describe steps that optimized the procedure and resources that will facilitate the development of direct IBD mapping.

Base Pair Mismatch↗

PubMed2003

Natural variation in human gene expression assessed in lymphoblastoid cells.

The sequencing of the human genome has resulted in greater attention to genetic variation among individuals, and variation at the DNA sequence level is now being extensively studied. At the same time, it has become possible to study variation at the level of gene expression by various methods. At present, it is largely unknown how widespread this variation in transcript levels is over the entire genome and to what extent individual differences in expression level are genetically determined. In the present study, we used lymphoblastoid cells to examine variation in gene expression and identified genes whose transcript levels differed greatly among unrelated individuals. We also found evidence for familial aggregation of expression phenotype by comparing variation among unrelated individuals, among siblings within families and between monozygotic twins. These observations suggest that there is a genetic contribution to polymorphic variation in the level of gene expression.

Female↗

PubMed2002

Gene expression phenotype in heterozygous carriers of ataxia telangiectasia.

The defining characteristic of recessive diseases is the absence of a phenotype in the heterozygous carriers. Nonetheless, subtle manifestations may be detectable by new methods, such as expression profiling. Ataxia telangiectasia (AT) is a typical recessive disease, and individual carriers cannot be reliably identified. As a group, however, carriers of an AT disease allele have been reported to have a phenotype that distinguishes them from normal control individuals: increased radiosensitivity and risk of cancer. We show here that the phenotype is also detectable, in lymphoblastoid cells from AT carriers, as changes in expression level of many genes. The differences are manifested both in baseline expression levels and in response to ionizing radiation. Our findings show that carriers of a recessive disease may have an "expression phenotype." In the particular case of AT, this suggests a new approach to the identification of carriers and enhances understanding of their increased cancer risk. More generally, we demonstrate that genomic technologies offer the opportunity to identify and study unaffected carriers, who are hundreds of times more common than affected patients.

Ataxia Telangiectasia↗