Genetics

Psychiatric Genetics

2009-04-15T23:19:00.000-07:00

Introduction

Schizophrenia (SCZ) and bipolar affective disorder (BPAD) are severe, disabling psychiatric illnesses that feature prominently in the top ten causes of disability world wide. Research into the causes of these devastating disorders and the development of improved interventions is a high scientific, social, individual and public health priority.

As yet, little is known with any certainty about their cellular and molecular basis, but family, twin and adoption studies indicate that, although inheritance patterns are complex, major psychiatric illness has a significant genetic component. For example, the risk to a first-degree relative of an affected person is increased tenfold over that of the general population and several chromosomal regions that are likely to harbour susceptibility genes for these disorders have been identified. Family, twin and adoption studies have also shown that there is a genetic relationship between different psychiatric phenotypes, implying that some genetic risk factors may contribute to a range of psychotic symptoms, and give rise to phenotypes that cross the traditional diagnostic boundaries of SCZ and affective disorders.

Research

Our work aims to identify gene variants that increase susceptibility to SCZ and BPAD. The mode of inheritance of the major psychoses is complex, demonstrating incomplete penetrance, and, in all likelihood, extensive locus heterogeneity and oligo or polygenicity. A prevailing genetic model for psychosis is a quantitative trait locus (QTL) model that invokes the interaction of several genes of small effect. However, in common with other complex disorders including breast cancer, colon cancer, diabetes and Alzheimer's disease, there is also growing evidence that psychosis can arise from the inheritance of mutations with large effect and strong genotype-phenotype correlations (a quasi-Mendelian subset).

There is support for a quasi-Mendelian subset in the psychoses from extended pedigree studies. For example, in BPAD significant linkage has been reported in extended pedigrees on chromosomes 1q, 4p, 4q, 12q, 18q, 21q (Potash and DePaulo, 2000).. These types of study have been criticised because of inconsistent replications in genome scans of affected sibling pairs or large collections of small families. Failure to replicate could be due to lack of power of existing sample sets to detect alleles of small effect, and/or to the presence of substantial locus heterogeneity.

Thus it remains to be determined where the balance lies between the models of Mendelian inheritance with genetic heterogeneity and a fully quantitative model. However, it is exciting that for the first time, we have access to both adequate technology and well-documented sample sets with which to rigorously test and compare these alternative models.

Approaches

We take two main approaches to the initial identification of susceptibility loci. The first involves the identification and analysis of genes affected by chromosomal rearrangements, such as translocations and deletions. The second involves linkage analysis of pedigrees where psychiatric illness segregates as a quasi-Mendelian trait. All of this work is carried out via a long-standing collaboration with Prof Douglas Blackwood and Dr Walter Muir at the Dept. of psychiatry of Edinburgh) who provide clinical expertise and access to biological samples from families, parent offspring trios and case control samples.

WTCRF Genetics Core

The WTCRF Genetics Core is staffed and equipped to provide secure receipt, processing, archiving and analysis of biological samples. With well defined SOPs and sophisticated automation the WTCRF Genetics Core offers a high quality, high throughput service to all researchers.

The Genetics Core aims to provide an accurate, reliable and efficient service that can be tailored to an individual project.”

Our main services include:

Epidemiology and genetics of stroke and its subtypes

2009-04-15T23:10:00.000-07:00

Introduction

Stroke is the second commonest cause of death worldwide after coronary heart disease, and is a major cause of disability. The clinical burden and cost of stroke are at least as great as those due to heart disease or cancer, and are projected to increase rapidly as populations age. It affects mainly elderly people:

about half of all strokes occur in those over the age of 75.

Stroke (or 'brain attack') is a clinical syndrome, presenting with a rapid onset of focal (or at times global) dysfunction of the brain, caused by abrupt interruption of blood

supply to the brain because of a blocked or ruptured artery. There are three main pathological types. 80% of all strokes are ischaemic, while about 15% are due to intracerebral haemorrhage and 5% to subarachnoid haemorrhage. Each of these pathological types has various subtypes, whose underlying vascular pathology is

incompletely understood.

Our group is using a variety of epidemiological methods to attempt to:

better understand the vascular pathologies underlying stroke subtypes (the stroke phenotype)
establish which genes do (and do not) contribute to the risk of stroke, its subtypes, and various intermediate phenotypes.

Understanding stroke subtypes

We are particularly interested in how differences and similarities in risk factors and prognosis between lacunar (small vessel disease) stroke and other ischaemic stroke subtypes may inform us about the underlying vascular pathology. We are exploring these through a series of systematic reviews and meta-analyses, collaborative individual patient data analyses, and analyses of data from over 2500 patients in our hospital-based stroke register, the Edinburgh Stroke Study.

Stroke genetics:

About two thirds of stroke risk can be explained by variation in known risk factors: blood pressure, smoking, overweight, cholesterol, diet, physical inactivity, alcohol. While much of the risk of stroke is due to environmental influences ('nurture'), genetic factors ('nature') also have an important role. They may

directly affect known risk factors (e.g. by increasing blood pressure), modify known or unknown environmental influences (so-called 'gene-environment interaction'), or act through completely novel pathways. The genetic component of stroke is currently poorly understood, but many genes are probably involved, each exerting only a modest effect on the overall risk. Reliably identifying these genes is very important, since it may:

increase our understanding of already known risk factors and how to influence them;
identify previously unknown pathways that influence stroke risk;
help us better to understand the differences between pathological types and subtypes of stroke.

We are using systematic review and meta-analysis methodology to assess the strength of the evidence for the contribution of various candidate genes to the risk of stroke, its subtypes and various intermediate phenotypes, including carotid intima-media thickness, leukoaraiosis and brain microbleeds.

Over the last few years we have collected DNA from around 1800 well-phenotyped patients in the Edinburgh Stroke Study (above), for genetic case-control and intermediate phenotype studies. We plan to perform these studies in collaboration with colleagues in the Edinburgh, and other groups in the UK and further afield.

Our work has been made possible through the support of the Wellcome Trust Clinical Research Facility, and funding from the Wellcome Trust, the Binks Trust, the Edinburgh Stroke Research Endowment Fund, and the School of Molecular and Clinical Medicine Strategic Research Fund.

Research and technology

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Model organisms and genetics

Although geneticists originally studied inheritance in a wide range of organisms, researchers began to specialize in studying the genetics of a particular subset of organisms. The fact that significant research already existed for a given organism would encourage new researchers to choose it for further study, and so eventually a few model organisms became the basis for most genetics research. Common research topics in model organism genetics include the study of gene regulation and the involvement of genes in development and cancer.

Organisms were chosen, in part, for convenience - short generation times and easy genetic manipulation made some organisms popular genetics research tools. Widely used model organisms include the gut bacterium Escherichia coli, the plant Arabidopsis thaliana, baker's yeast (Saccharomyces cerevisiae), the nematode Caenorhabditis elegans, the common fruit fly (Drosophila melanogaster), and the common house mouse (Mus musculus).

Medical genetics research

Medical genetics seeks to understand how genetic variation relates to human health and disease. When searching for an unknown gene that may be involved in a disease, researchers commonly use genetic linkage and genetic pedigree charts to find the location on the genome associated with the disease. At the population level, researchers take advantage of Mendelian randomization to look for locations in the genome that are associated with diseases, a technique especially useful for multigenic traits not clearly defined by a single gene.[65] Once a candidate gene is found, further research is often done on the same gene (called an orthologous gene) in model organisms. In addition to studying genetic diseases, the increased availability of genotyping techniques has led to the field of pharmacogenetics - studying how genotype can affect drug responses.

Although it is not an inherited disease, cancer is also considered a genetic disease.[67] The process of cancer development in the body is a combination of events. Mutations occasionally occur within cells in the body as they divide - while these mutations will not be inherited by any offspring, they can affect the behavior of cells, sometimes causing them to grow and divide more frequently. There are biological mechanisms that attempt to stop this process - signals are given to inappropriately dividing cells that should trigger cell death, but sometimes additional mutations occur that cause cells to ignore these messages. An internal process of natural selection occurs within the body and eventually mutations accumulate within cells to promote their own growth, creating a cancerous tumor that grows and invades various tissues of the body.

Research techniques
DNA can be manipulated in the laboratory. Restriction enzymes are a commonly used enzyme that cuts DNA at specific sequences, producing predictable fragments of DNA.[68] The use of ligation enzymes allows these fragments to be reconnected, and by ligating fragments of DNA together from different sources, researchers can create recombinant DNA. Often associated with genetically modified organisms, recombinant DNA is commonly used in the context of plasmids - short circular DNA fragments with a few genes on them. By inserting plasmids into bacteria and growing those bacteria on plates of agar (to isolate clones of bacteria cells), researchers can clonally amplify the inserted fragment of DNA (a process known as molecular cloning). (Cloning can also refer to the creation of clonal organisms, through various techniques.)

DNA can also be amplified using a procedure called the polymerase chain reaction (PCR). By using specific short sequences of DNA, PCR can isolate and exponentially amplify a targeted region of DNA. Because it can amplify from extremely small amounts of DNA, PCR is also often used to detect the presence of specific DNA sequences.

DNA sequencing and genomics

One of the most fundamental technologies developed to study genetics, DNA sequencing allows researchers to determine the sequence of nucleotides in DNA fragments. Developed in 1977 by Frederick Sanger and coworkers, chain-termination sequencing is now routinely used to sequence DNA fragments. With this technology, researchers have been able to study the molecular sequences associated with many human diseases.

As sequencing has become less expensive and with the aid of computational tools, researchers have sequenced the genomes of many organisms by stitching together the sequences of many different fragments (a process called genome assembly). These technologies were used to sequence the human genome, leading to the completion of the Human Genome Project in 2003. New high-throughput sequencing technologies are dramatically lowering the cost of DNA sequencing, with many researchers hoping to bring the cost of resequencing a human genome down to a thousand dollars.

The large amount of sequences available has created the field of genomics, research that uses computational tools to search for and analyze patterns in the full genomes of organisms. Genomics can also be considered a subfield of bioinformatics, which uses computational approaches to analyze large sets of biological data.

Recombination and linkage

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The diploid nature of chromosomes allows for genes on different chromosomes to assort independently during sexual reproduction, recombining to form new combinations of genes. Genes on the same chromosome would theoretically never recombine, however, were it not for the process of chromosomal crossover. During crossover, chromosomes exchange stretches of DNA, effectively shuffling the gene alleles between the chromosomes. This process of chromosomal crossover generally occurs during meiosis, a series of cell divisions that creates haploid germ cells that later combine with other germ cells to form child organisms.

The probability of chromosomal crossover occurring between two given points on the chromosome is related to the distance between them. For an arbitrarily long distance, the probability of crossover is high enough that the inheritance of the genes is effectively uncorrelated. For genes that are closer together, however, the lower probability of crossover means that the genes demonstrate genetic linkage - alleles for the two genes tend to be inherited together. The amounts of linkage between a series of genes can be combined to form a linear linkage map that roughly describes the arrangement of the genes along the chromosome.

Reproduction

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When cells divide, their full genome is copied and each daughter cell inherits one copy. This process, called mitosis, is the simplest form of reproduction and is the basis for asexual reproduction. Asexual reproduction can also occur in multicellular organisms, producing offspring that inherit their genome from a single parent. Offspring that are genetically identical to their parents are called clones.

Eukaryotic organisms often use sexual reproduction to generate offspring that contain a mixture of genetic material inherited from two different parents. The process of sexual reproduction alternates between forms that contain single copies of the genome (haploid) and double copies (diploid). Haploid cells fuse and combine genetic material to create a diploid cell with paired chromosomes. Diploid organisms form haploids by dividing, without replicating their DNA, to create daughter cells that randomly inherit one of each pair of chromosomes. Most animals and many plants are diploid for most of their lifespan, with the haploid form reduced to single cell gametes.

Although they do not use the haploid/diploid method of sexual reproduction, bacteria have many methods of acquiring new genetic information. Some bacteria can undergo conjugation, transferring a small circular piece of DNA to another bacterium. Bacteria can also take up raw DNA fragments found in the environment and integrate them into their genome, a phenomenon known as transformation. This processes result in horizontal gene transfer, transmitting fragments of genetic information between organisms that would otherwise be unrelated.

DNA and chromosomes

2008-07-12T04:18:00.000-07:00

The molecular basis for genes is deoxyribonucleic acid (DNA). DNA is composed of a chain of nucleotides, of which there are four types: adenine (A), cytosine (C), guanine (G), and thymine (T). Genetic information exists in the sequence of these nucleotides, and genes exist as stretches of sequence along the DNA chain. Viruses are the only exception to this rule - sometimes viruses use the very similar molecule RNA instead of DNA as their genetic material.

DNA normally exists as a double-stranded molecule, coiled into the shape of a double-helix. Each nucleotide in DNA preferentially pairs with its partner nucleotide on the opposite strand: A pairs with T, and C pairs with G. Thus, in its two-stranded form, each strand effectively contains all necessary information, redundant with its partner strand. This structure of DNA is the physical basis for inheritance: DNA replication duplicates the genetic information by splitting the strands and using each strand as a template for synthesis of a new partner strand.

Genes are arranged linearly along long chains of DNA sequence, called chromosomes. In bacteria, each cell has a single circular chromosome, while eukaryotic organisms (which includes plants and animals) have their DNA arranged in multiple linear chromosomes. These DNA strands are often extremely long; the largest human chromosome, for example, is about 247 million base pairs in length. The DNA of a chromosome is associated with structural proteins that organize, compact, and control access to the DNA, forming a material called chromatin; in eukaryotes chromatin is usually composed of nucleosomes, repeating units of DNA wound around a core of histone proteins. The full set of hereditary material in an organism (usually the combined DNA sequences of all chromosomes) is called the genome.

While haploid organisms have only one copy of each chromosome, most animals and many plants are diploid, containing two of each chromosome and thus two copies of every gene. The two alleles for a gene are located on identical loci of sister chromatids, each allele inherited from a different parent.

An exception exists in the sex chromosomes, specialized chromosomes many animals have evolved that play a role in determining the sex of an organism. In humans and other mammals the Y chromosome has very few genes and triggers the development of male sexual characteristics, while the X chromosome is similar to the other chromosomes and contains many genes unrelated to sex determination. Females have two copies of the X chromosome, but males have one Y and only one X chromosome - this difference in X chromosome copy numbers leads to the unusual inheritance patterns of sex-linked disorders.

Interactions of multiple genes

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Organisms have thousands of genes, and in sexually reproducing organisms assortment of these genes are generally independent of each other. This means that the inheritance of an allele for yellow or green pea color is unrelated to the inheritance of alleles for white or purple flowers. This phenomenon, known as "Mendel's second law" or the "Law of independent assortment", means that the alleles of different genes get shuffled between parents to form offspring with many different combinations. (Some genes do not assort independently, demonstrating genetic linkage, a topic discussed later in this article.)

Often different genes can interact in a way that influences the same trait. In the Blue-eyed Mary (Omphalodes verna), for example, there exists a gene with alleles that determine the color of flowers: blue or magenta. Another gene, however, controls whether the flowers have color at all: color or white. When a plant has two copies of this white allele, its flowers are white - regardless of whether the first gene has blue or magenta alleles. This interaction between genes is called epistasis, with the second gene epistatic to the first.

Many traits are not discrete features (eg. purple or white flowers) but are instead continuous features (eg. human height and skin color). These complex traits are the product of many genes. The influence of these genes is mediated, to varying degrees, by the environment an organism has experienced. The degree to which an organism's genes contribute to a complex trait is called heritability. Measurement of the heritability of a trait is relative - in a more variable environment, the environment has a bigger influence on the total variation of the trait. For example, human height is a complex trait with a heritability of 89% in the United States. In Nigeria, however, where people experience a more variable access to good nutrition and health care, height has a heritability of only 62%.

Discrete inheritance and Mendel's laws

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At its most fundamental level, inheritance in organisms occurs by means of discrete traits, called genes. This property was first observed by Gregor Mendel, who studied the segregation of heritable traits in pea plants. In his experiments studying the trait for flower color, Mendel observed that the flowers of each pea plant were either purple or white - and never an intermediate between the two colors. These different, discrete versions of the same gene are called alleles.

In the case of pea plants, each organism has two alleles of each gene, and the plants inherit one allele from each parent. Many organisms, including humans, have this pattern of inheritance. Organisms with two copies of the same allele are called homozygous, while organisms with two different alleles are heterozygous.

The set of alleles for a given organism is called its genotype, while the observable trait the organism has is called its phenotype. When organisms are heterozygous, often one allele is called dominant as its qualities dominate the phenotype of the organism, while the other allele is called recessive as its qualities recede and are not observed. Some alleles do not have complete dominance and instead have incomplete dominance by expressing an intermediate phenotype, or codominance by expressing both alleles at once.

When a pair of organisms reproduce sexually, their offspring randomly inherit one of the two alleles from each parent. These observations of discrete inheritance and the segregation of alleles are collectively known as Mendel's first law or the Law of Segregation.

Molecular genetics

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Although genes were known to exist on chromosomes, (chromosomes are composed of both protein and DNA) scientists did not know which of these was responsible for inheritance. In 1928, Frederick Griffith discovered the phenomenon of transformation (see Griffith's experiment): dead bacteria could transfer genetic material to "transform" other still-living bacteria. Sixteen years later, in 1944, Oswald Theodore Avery, Colin McLeod and Maclyn McCarty identified the molecule responsible for transformation as DNA. Hershey-Chase experiment in 1952 also showed that DNA (rather than protein) was the genetic material of the viruses that infect bacteria, providing further evidence that DNA was the molecule responsible for inheritance.

James D. Watson and Francis Crick solved the structure of DNA in 1953, using the X-ray crystallography work of Rosalind Franklin that indicated DNA had a helical structure (ie. shaped like a corkscrew). Their double-helix model had two strands of DNA with the nucleotides pointing inwards, each matching a complementary nucleotide on the other strand to form what looks like rungs on a twisted ladder. This structure showed that genetic information exists in the sequence of nucleotides on each strand of DNA. The structure also suggested a simple method for duplication: if the strands are separated, new partner strands can be reconstructed for each based on the sequence of the old strand.

Although the structure of DNA showed how inheritance worked, it was still not known how DNA influenced the behavior of cells. In the following years scientists tried to understand how DNA controls the process of protein production. It was discovered that the cell uses DNA as a template to create matching messenger RNA (a molecule with nucleotides, very similar to DNA). The nucleotide sequence of a messenger RNA is used to create an amino acid sequence in protein; this translation between nucleotide and amino acid sequences is known as the genetic code.

With this molecular understanding of inheritance, an explosion of research became possible. One important development was chain-termination DNA sequencing in 1977 by Frederick Sanger: this technology allows scientists to read the nucleotide sequence of a DNA molecule. In 1983, the polymerase chain reaction was developed by Kary Banks Mullis, providing a quick way to isolate and amplify a specific section of a DNA from a mixture. These and other techniques, through the pooled efforts of the Human Genome Project and parallel private effort by Celera Genomics, culminated in the sequencing of the human genome in 2003.

Mendelian and classical genetics

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The modern science of genetics traces its roots to Gregor Johann Mendel, a German-Czech Augustinian monk and scientist who studied the nature of inheritance in plants. In his paper "Versuche über Pflanzenhybriden" ("Experiments on Plant Hybridization"), presented in 1865 to the Naturforschender Verein (Society for Research in Nature) in Brünn, Mendel traced the inheritance patterns of certain traits in pea plants and showed that they could be described mathematically.[6] Although this pattern of inheritance could only be observed for a few traits, Mendel's work suggested that heredity was both particulate, not acquired, and that the inheritance patterns of many traits could be explained through simple rules and ratios.

The importance of Mendel's work was not understood until early in the 1900s, after his death, when his research was re-discovered by other scientists working on similar problems. The word genetics itself was coined in 1905 by William Bateson, a proponent of Mendel's work. (The adjective genetic, derived from the Greek word genno (γεννώ): to give birth, predates the noun and was first used in a biological sense in 1860.) Bateson popularized the usage of the word genetics to describe the study of inheritance in his inaugural address to the Third International Conference on Plant Hybridization in London, England, in 1906.

After the rediscovery of Mendel's work, scientists tried to discover which molecules in the cell were responsible for inheritance. In 1910 Thomas Hunt Morgan argued that genes are on chromosomes, based on observations of a sex-linked white eye mutation in fruit flies. In 1913 his student Alfred Sturtevant used the phenomenon of genetic linkage to show that genes are arranged linearly on the chromosome.

History of Genetics

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Although the science of genetics began with the work of Gregor Mendel in the mid-1800s, there were some theories of inheritance that preceded Mendel. A popular theory during Mendel's time was the concept of blending inheritance: the idea that individuals inherit a smooth blend of traits from their parents. Mendel's work disproved this, showing that traits are composed of combinations of distinct genes rather than a continuous blend. Also popular at the time was the theory of inheritance of acquired characteristics: the belief that individuals inherit traits that have been strengthened in their parents. This theory (commonly associated with Jean-Baptiste Lamarck) is now known to be wrong, the experiences of individuals do not affect the genes they pass to their children. Other theories included the pangenesis of Charles Darwin, which had both acquired and inherited aspects, and Francis Galton's reformulation of pangenesis as both particulate and inherited.

Genetics

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Genetics, a discipline of biology, is the science of heredity and variation in living organisms.The fact that living things inherit traits from their parents has been used since prehistoric times to improve crop plants and animals through selective breeding. However, the modern science of genetics, which seeks to understand the process of inheritance, only began with the work of Gregor Mendel in the mid-nineteenth century. Although he did not know the physical basis for heredity, Mendel observed that organisms inherit traits in a discrete manner - these basic units of inheritance are now called genes.
Genes correspond to regions within DNA, a molecule composed of a chain of four different types of nucleotides - the sequence of these nucleotides is the genetic information organisms inherit. DNA naturally occurs in a double stranded form, with nucleotides on each strand complementary to each other. Each strand can act as a template for creating a new partner strand - this is the physical method for making copies of genes that can be inherited.

The sequence of nucleotides in a gene is translated by cells to produce a chain of amino acids, creating proteins - the order of amino acids in a protein corresponds to the order of nucleotides in the gene. This is known as the genetic code. The amino acids in a protein determine how it folds into a three-dimensional shape; this structure is, in turn, responsible for the protein's function. Proteins carry out almost all the functions needed for cells to live. A change to the DNA in a gene can change a protein's amino acids, changing its shape and function: this can have a dramatic effect in the cell and on the organism as a whole.

Although genetics plays a large role in the appearance and behavior of organisms, it is the combination of genetics with what an organism experiences that determines the ultimate outcome. For example, while genes play a role in determining a person's height, the nutrition and health that person experiences in childhood also have a large effect.