Lkl

Association study using case-control design Resolution from association analysis is much finer as the allelic architecture of the population sampled is based on many historical recombination and mutational events. The haplotype on which the functional mutation arose breaks down over time. Figure 2.4 Genetic association analysis. Genetic association studies sample from a population in which many historical recombination and mutational events will have occurred allowing increased resolution from...

Info

Aneuploidy refers to the state of having an abnormal number of individual chromosomes. This may involve loss of a chromosome pair (nullisomy) or single chromosome (monosomy) or gain of a chromosome pair (tetrasomy) or single chromosome (trisomy). Segmental aneusomy involves a portion of a chromosome. Polyploidy involves having more than the normal complement of two chromosome sets (diploidy, 2n). Cells may, for example, be triploid (3n) or tetraploid (4n). There are 22 pairs of autosomes,...

Dkv

Based on transcript levels but protein levels are of greater relevance to determining a particular cellular and whole organism phenotype. The observed abundance of a given protein will be dependent on many factors following transcription, and indeed changes at the RNA level may not be reflected in protein abundance and vice versa. For example, observed circulating plasma or serum concentration of a particular protein will depend on a complex series of factors ranging from genetic and epigenetic...

Cataloguing human genetic variation

From early cytogenetic studies revealing major chromosomal abnormalities to more recent analysis of smaller scale structural and fine scale sequence level variation, remarkable diversity in our individual genetic makeup has been demonstrated. The establishment of clear terminology for use in reporting such variation is essential to the continued advancement ofthe field, and has been highlighted by many investigators. The classification based on size advocated by Scherer and Lee (Fig. 1.29)...

Box Satellites minisatellites and microsatellites

Satellite DNA comprises very long arrays of tandem repeats typically 100 kb to several megabases in size, the repeat unit length varying between 5 and 171 bp. Minisatellite DNA arrays are of intermediate size and typically span between 100 bp and 20 kb, with each repeat unit between 6 and 100 bp in length. Microsatellite DNA comprises short arrays less than 100 bp in size, made up of simple tandem repeats 1-6 bp in length. There is, however, some blurring in the distinction between...

Genetic variation and alternative splicing

In this chapter the relationship between gene expression and genetic variation has been explored with strong evidence of heritable differences in expression which can be mapped to specific genomic loci, local or distant to the gene encoding the transcript whose abundance has been quantified. But in terms of the transcript, what has been measured For the majority of human genes, several different mRNAs will be expressed as a result of alternative splicing (Section 11.6.1). The occurrence of...

Functional effects of minisatellites

The functional consequences of minisatellites can be diverse, ranging from differences in protein structure and function by altering open reading frames (ORFs), to effects on transcription (Nakamura et al. 1998). Gene transcription may be modulated by specific minisatellites, as seen at the INS gene (Section 7.3.3). Effects on transcription have also been found involving a minisatellite in an enhancer element 3.8 kb upstream from the transcription start site of the ABO blood group gene...

Gene deserts and other loci

The finding of disease associations with SNP markers in regions without any genes (so-called 'gene deserts') is seen for several loci in Crohn's disease as well as other diseases studied by genome-wide association scans. The loci appear highly significant and reproducible in replication studies. For example, Libioulle and colleagues in a genome-wide association scan used 302 000 SNPs to analyse 547 cases and 928 controls in a Belgian population (Libioulle et al. 2007). They found three loci to...

Sickle Cell Anemia

A number sign ( ) is used with this entry because sickle cell anemia is the result of mutant beta globin (HBB 141900 in which the mutation causes sickling of hemoglobin rather than reduced amount of beta globin which causes beta-thalassemia. The most common cause of sickle cell anemia is Hb S (141900.0243), with SS disease being most prevalent in Africans. CLINICAL FEATURES Scriver and Waugh (1930) reported detailed studies of a 7-year old child with sickle cell anemia. Her main complaints were...

Mcm

And colleagues analysed 52 patients and found that lactase activity was strongly associated with genotype, with the highest activity being seen among individuals homozygous for the T-13910 and A-22018 alleles (Fig. 10.5). The investigators were also able to assay the ratio of lactase to sucrase activity and found similar results, segregating according to underlying genotype. Finally, the team analysed allele-sperific gene expression at the RNA level, comparing relative expression within...

Malaria genetic diversity and selection

13.2.1 Inherited factors and resistance to malaria Malaria is one of the most important infectious diseases in the world and a leading cause of death, particularly among children. Genetic variation in man is an important determinant of disease susceptibility but has to be considered as part of a remarkably complex multifactorial disorder involving diversity in the mosquito vector, parasites, and environment as well as our own immune response (Box 13.1). The complexity of the relationship...

I

On codon Met> Val on codon Met> Arg o n cod on M et> Lys on codon Met> Thr on codon Met> Ile on codon Met> Ile o n codo n M et> Ile (HbVar A database of Human Hemoglobin Variants and Thalassemias) 5'UTR +33 (C-> G) beta+ (silen t) beta nt 33 C> G Initiation codon AT-G> GTG beta 0 beta In Initiation codon AT-G> AGG beta 0 beta In Initiation codon T> A beta In Initiation codon AT-G> ACG betaO beta In Initiation codo Initiation codon AT-G> ATT beta 0 beta In Initiation...

Genetic diversity in TRIMa gives insights into the impact of retroviruses during primate evolution

Retroviruses have been colonizing vertebrate hosts for hundreds of millions of years, leaving a calling card of integrated retroviral sequence transmitted between generations (Gifford and Tristem 2003). An early discovery in research into the current HIV-1 pandemic was the finding that this particular retrovirus had a limited host range, being restricted to humans and apes. The barrier to infection in other primate cells was identified in 2004 as being mediated by a protein named TRIM5a, which...

Rlt

Figure 11.8 Genome-wide association for genes involved in the immune response as defined by Gene Ontology analysis. Genes showing genome-wide significance (lod score > 6) are indicated with gene names either in cis within 100 kb of the gene, or in cis on the same chromosome but more than 100 kb away (gene name underlined), or in trans (gene name in grey). Data are plotted by genome position (x axis) with the lod score of association on the y axis. Reprinted by permission from Macmillan...

Surveying SNP diversity lessons from the SNP Consortium and Human Genome Project

Prior to publication of the draft human genome sequence in 2001, a number of studies demonstrated that large scale identification of SNPs and their high throughput genotyping was possible. In 1998, Lander and colleagues published a large scale SNP analysis in which they demonstrated the utility of resequencing strategies and DNA 'chip' arrays for SNP discovery, while also showing how such arrays could be extended to allow high throughput genotyping (Wang et al. 1998). Resequencing over 279 kb...

Local and distant regulatory variation

Use of the terms 'cis' and 'trans' acting is however open to some ambiguity if based only on the genomic location of the mapped genetic marker in relation to the specific gene encoding the transcript whose expression has been quantified. This relationship alone does not define mechanism and indeed there is significant variation between studies in what is considered 'cis-acting' on this basis, whether it is the mapped markers closest to the gene encoding the assayed transcript (Emisson et al....

Box Codon position and degeneracy

Sites where all possible substitutions are synonymous are also known as 'four-fold degenerate' sites and are relatively common in frequency compared to other coding changes such that their frequency is similar to substitution rates within introns. 'Two-fold degenerate' sites refer to positions where one of three potential base substitutions is synonymous. Non-degenerate, four-fold degenerate, and two-fold degenerate sites make up 65 , 16 , and 19 respectively of the base positions in human...

Contents

1.2 Genetic variation and a molecular basis for disease 3 1.2.1 A difference at the protein level between haemoglobin molecules 3 Box 1.2 Sickle cell disease 3 Box 1.3 Genotype and phenotype 3 Box 1.4 Chromosomes 4 Box 1.5 Genes 5 Box 1.6 An amino acid difference responsible for Hb S 6 1.2.2 Mendelian inheritance, alleles and traits 6 Box 1.7 Phenotype of sickle cell disease 7 Box 1.8 Alleles 8 1.2.3 Sequencing the HBB gene and defining the variant responsible for Hb S 9 Box 1.9 DNA structure...

Genetic diversity in Hla Kir and HIV strategies for survival

Viral co-evolution with molecules of the immune system is thought to have been a major force in shaping the genetic diversity observed today in genes involved in our immune defence. The consequences of this are seen in the human leukocyte antigen (HLA) genes where particular alleles have been found to be associated with differences in disease progression after infection with HIV-1. Research in this field has provided evidence to support the hypothesis of 'heterozygous advantage' (also called...

Structural variants of haemoglobin and the thalassaemias

Structural variants of haemoglobin are incredibly diverse with over 980 described (http globin.cse.psu.edu hbvar menu.html) (Giardine et al. 2007). Mainly they arise due to single amino acid substitutions in the globin protein sequence, with a few examples of lengthening or shortening of the globin chain (Fig. 1.21) (Weatherall 2001 Old 2006). Hb S is an example of a structural haemoglobin variant common in sub-Saharan Africa, the Mediterranean, Middle East, and India. Other variants Genomic y...

Characteritic Of Gene

Laws of inheritance with traits passed as distinct discrete entities between generations, with trait variation because inheritable factors (Mendel 1865) Nucleic acids isolated (Miescher 1869) 'Gene' (from Greek 'genesis' or 'genos') used to describe determining factor in gamete for a characteritic (Johannsen 1909) Linear model of genes on a chromosome ('beads on a string') (Morgan 1910) First genetic map (Sturtevant 1913) Heredity recognised to have a physical basis - Xrays lead to mutations...

DNA fingerprinting

Dna Fingerprint

In 1985, Jeffreys and colleagues published a series of papers highlighting the high level of polymorphism in the number of repeats found at certain minisatellites, and their utility in defining a unique pattern for a particular individual - an approach dubbed 'DNA fingerprinting' (Jeffreys et al. 1985b, 1985c). They found that a particular 33 bp repeat present in a short minisatellite of four tandem repeats within an intron of the myoglobin gene could be used to generate a probe that detected a...

Functional consequences of microsatellites

Short tandemly repeated sequences may significantly alter the control of gene expression or the structure and function of the encoded protein. The underlying mechanisms and pathophysiological consequences of microsatellite diversity have been best characterized for unstable repeat expansions, which can result in severe neurological disease (reviewed in Section 7.6), while microsatellite instability has also been associated with cancer (Box 7.7). Microsatellite dinucleotide repeats have been...

Genetic diversity involving the globin genes

The variant responsible for Hb S is only one of a remarkable number of differences in DNA sequence i dentified within HBB (Fig. 1.20) and move broadly across the a globin and globin gene clusters on chromosomes 16 and 11 (see Fig. 1.1). Such variation underlies not only structural variants of haemoglobin but also differences in globin synthesis leading to thalassaemia. Analysis of genetic diversity in the globin loci has served to define many of the different classes of variation now recognized...

Satellite DNA

Satellite Dna

Satellite DNA comprises very large arrays of tandemly repeated noncoding DNA, usually megabases in size, which form the major structural constituent of hetero-chromatin, a tightly packaged condensed state of transcriptionally suppressed DNA. Satellite DNA is the main component of functional centromeres, as well as het-erochromatin in pericentromeric and telomeric regions, and in the short arms of the acrocentric chromosomes (chromosomes 13, 14, 15, 21, and 22) (Charlesworth et al. 1994 Schueler...

S

Box 6.9 Rhesus blood group and disease The Rh blood group system was discovered in the late 1930s (Levine and Stetson 1939 Landsteiner and Wiener 1940). The name relates to the experiments of Landsteiner and Weiner involving the rhesus macaque when rabbits were immunized with rhesus monkey cells an antibody was produced that agglutinated human red blood cells (Landsteiner and Wiener 1940). Rh blood group was found to be of considerable clinical importance, in particular to be responsible for...

Genetic diversity and susceptibility to Leishmaniasis in mouse and man

Genetic variation also appears to play an important role in modulating susceptibility to a second major parasitic disease, leishmaniasis Box 13.4 . Evidence from mouse models highlighted a role for genetic factors in susceptibility to infection Lipoldova and Demant 2006 . Among humans, studies of visceral leishmaniasis in northeastern Brazil provided evidence of familial aggregation and increased risk in siblings of affected sib pairs Cabello et al. 1995 Peacock et al. 2001 . Variation between...

Hbb

Figure 1.20 Sequence variation in HBB. The DNA sequence of HBB has been found to be remarkably diverse, with many nonsynonymous variants resulting in amino acid changes. Single amino acid substitutions have been reported in at least 138 out of 146 codons in p globin with over 335 different single nucleotide changes as well as concurrent variants, insertions, and deletions Huisman et al. 1996 . The portion of the figure showing sequences, genomic location, and SNPs was adapted from a screenshot...

Box Transposable elements and exaptation

There are now a number of examples where relics of transposable elements can acquire functions that are advantageous to their host genome. A neuronal enhancer of the proopiomelanocortin POMC gene is thought to have arisen from a CORE-SINE retro-transposon some 170 million years ago in the lineage leading to mammals Santangelo et al. 2007 . This group of SINEs lost transposable activity about 100 million years ago in placental mammals where their estimated copy number is 300 000 but remained...

DNA transposons a fossil record in the genome

DNA transposons have only relatively recently been recognized in humans Morgan 1995 Oosumi et al. 1995 Smit and Riggs 1996 . They are thought to constitute 3 of the human genome Lander et al. 2001 . Active DNA transposon elements found in species such as Drosophila are characterized by encoding a transposase gene and having terminal inverted repeat sequences to which the transposase enzyme binds. Transposase catalyses transposition by cutting and pasting van Luenen et al. 1994 . The transposase...

Box Phase I Hap Map populations

For phase I of the International HapMap Project, 270 individuals from four different populations were recruited. Two groups of individuals of Asian ancestry in geographic terms were genotyped 45 unrelated Han Chinese from Beijing, China, denoted the 'CHB' population, and 45 Japanese from Tokyo, Japan 'JPT' . For the other two populations studied, of African and European ancestry, each comprised of 30 parent-offspring trios a total of 90 individuals one cohort was from Yoruba in Ibadan, Nigeria...

HLAB and susceptibility to ankylosing spondylitis

By the early 1970s there were growing numbers of reports of association between the possession of particular HLA antigens on the surface of white blood cells and susceptibility to disease, notably coeliac disease, multiple myeloma, lymphoma, systemic lupus erythematosus, and psoriasis. During the course of the year in 1972, independently reproducible and highly significant associations were found between the possession of HL-A1 and HL-A8 and coeliac disease Falchuk et al. 1972 Stokes et al....

Coreceptor ligands and HIV

HIV-1 suppressing factors produced by CD8 T cells were identified in 1995 as the chemokines RANTES regulated on activation normal T cell expressed and secreted , MIP1a macrophage inflammatory protein-1 alpha , and MIPip Cocchi et al. 1995 . These chemokines were found to be natural ligands for the CCR5 coreceptor necessary for macrophage tropic viral entry, and are associated with HIV-1 transmission and disease progression see Fig. 14.4 Gallo et al. 1999 . RANTES inhibits in vitro replication...

Malaria parasites oxidative stress and GPD enzyme deficiency

It may seem remarkable that so many genetic variants are associated with resistance to malaria but this is considered to reflect the remarkably strong selective pressure exerted by malaria over recent human history. The enzyme glucose-6-phosphate dehydrogenase G6PD provides protection for the cell against oxidative damage, for example as a result of iron accumulating on the breakdown of haemoglobin by malaria parasites. Inherited deficiency of G6PD is commonly seen Box 13.2 and a striking...

HBB sequence diversity and sickle cell disease

Sequence diversity in the globin cluster plays an important part in the observed clinical heterogeneity in sickle cell disease for affected individuals when an individual inherits the Hb S variant on one allele and a different globin variant on the other. Thus while possessing two copies of Hb S is associated with the most severe disease, having a copy of Hb S combined with a chromosome with a non-functional HBB gene 0 thalassemia may be of comparable severity. Much less severe disease is...

Box DNA sequencing

In 1977 Maxam and Gilbert published a DNA sequencing method based on different chemical modifications of DNA such as dimethyl sulphate which then allowed cleavage of the DNA only at specific bases Maxam and Gilbert 1977 . The DNA was radio labelled and visualized by electrophoresis on a polyacrylamide gel, generating a ladder of fragments of different lengths terminating for example at 'A' nucleotides. Depending on the specific chemical modification used, other bases could be preferentially...

Hbq I Hba Lucl

Figure 1.26 Deletions removing regulatory elements leading to a thalassaemia. Schematic of a globin cluster and flanking region showing multispecies conserved sequences MCSs and DNase hypersensitive sites DHSs together with deletions affecting regulatory elements that result in a thalassaemia. The shortest region of overlap between the deletions is shown shaded and includes MCS-R1 and 2. Adapted with permission from Higgs and Wood 2008b .

Cytoadhesion and immune evasion host and parasite diversity

After the parasite invades a red blood cell, a race against time ensues in which the parasite seeks to multiply while avoiding detection and destruction by the human immune system. One parasite strategy involves cytoad-herence, parasitized red blood cells sticking to vascular endothelium or other cells to avoid passing through the spleen, which is very efficient at recognizing and removing infected cells from the circulation. This can be achieved by the parasite expressing specific proteins...

Ataagaac

Cluster of apparent Hardy-Weinberg disequilibrium Figure 4.6 Discovery of segregating deletions using SNP genotyping data. Cluster patterns within SNP genotyping data showing apparent mendelian inconsistency for a family trio, clusters of null genotypes, and clusters of apparent Hardy-Weinberg disequilibrium, provide a 'footprint' suggestive of segregating deletions. Redrawn and reprinted by permission from Macmillan Publishers Ltd Nature Genetics McCarroll et al. 2006 , copyright 2006.

Golden zebrafish mutants led to the identification of SLCA

As an illustration of how a gene locus showing strong evidence of positive selection within a particular population was determined, there are few examples more elegant than the work implicating the gene SLC24A5. Lamason and colleagues utilized the power of studying a model organism to identify a human gene within which the pattern of nucleotide diversity, and in particular a specific nucleotide substitution, played a major role in determining the light skinned pigmentation phenotype observed...

Autophagy and Crohns disease

An unexpected insight into disease pathogenesis was provided by the genome-wide associations found involving autophagy Box 9.6 , specifically with SNPs at ATG16L1 on chromosome 2q37 encoding ATG autophagy-re-lated 16-like protein, and IRGM at chromosome 5q33 encoding the immunity-related GTPase family M see Fig. 9.24 . Hampe and colleagues carried out a nonsynonymous SNP scan involving 7159 informative SNPs in 735 Crohn's disease cases and 368 controls with replication of the observed...

Apobecg an innate host defence mechanism against retroviral infection

Another part of our defence arsenal against retroviral infection after viral entry into cells was identified in humans in 2002 by Malim and colleagues as apolipo-protein B-editing catalytic polypeptide 3G APOBEC3G Sheehy et al. 2002 . It had been recognized since 1987 that the virion infectivity factor Vif protein of HIV-1 was essential for viral infectivity Fisher et al. 1987 Strebel et al. 1987 and that this protein was required to overcome a restriction factor encoded by the host cell Madani...

Copy number variation in health and susceptibility to disease

Submicroscopic structural genomic variation includes genomic alterations involving segments of DNA more than 1 kb in size and typically less than 3 Mb, which result in a change in DNA dosage, referred to as 'copy number variants' Box 4.1 , together with chromosomal rearrangements leading to a change in position or orientation Scherer et al. 2007 . In this chapter the particular focus is on copy number variants that include deletions, duplications, or insertions, and such genomic loci may be...

Lactase persistence in Middle Eastern populations

Consumption of camel milk may have driven selection for an additional major allele associated with lactase persistence among certain Middle Eastern populations in whom the Arabian camel Dromedary camelous is the main domesticated animal used as a source of milk Enattah et al. 2008 . Pastoralist groups in this region, such as among Saudi Arabians, have a high prevalence of lactase persistence, yet the European lactase persistence allele T-13910 is almost completely absent Cook and al-Torki 1975...

Transitions versus transversions

Nucleotide substitutions comprise either transversions or transitions Freese 1959 . The A to T substitution responsible for Hb S is an example of a transversion transversions involve substitutions of pyrimidines for purines, or purines for pyrimidines A C, A T, C- G, G- T . In contrast, transitions involve substitution of a pyrimidine for a pyrimidine C for T and vice versa, C T , or a purine for a purine A G . Based on the number of possible combinations, a ratio of 2 1 in the occurrence of...