L19- Quantitative genetics & multifactorial traits PDF

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Quantitative genetics & multifactorial traits...

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L19- 4BBY1070

QUALITATIVE GENETICS AND MULTIFACTORIAL GENES

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To understand that some traits are not distinct but display continuous variation. Such variation can be measured and described in quantitative terms. To appreciate that such traits are polygenic (the combined effect of various genes). To give examples of such traits. To understand that multifactorial traits are polygenic traits, that are also influenced by environment. Twin studies allow an estimation of heritability of traits in humans.

Polygenic inheritance: occurs when one characteristic is controlled by two or more genes. Often the genes are large in quantity but small in effect. Examples of human polygenic inheritance are height, skin colour, eye colour and weight. Continuous variation: - Is measured and describe in quantitative terms and known as quantitative inheritance. - The range of phenotypes results from the input of many genes - Referred to as polygenic traits - Quantitative traits influenced by many genes and environmental factors are referred to as multifactorial or complex traits. - Many traits are not distinct and clear cut and show a continuous range of phenotypes. Example of polygenic traits: - Eye colour 10 or more loci play a role in eye colour ¾ of eye colour variance is due to mutations in OCA2 loci A transporter protein found in the membranes of melanosomes Essential for melanin production Explaining quantitative traits in mendelian terms: - A and B contribute to pigment - a and b do not AaBb x AaBb

Polygenic inheritance when 3, 4 or 5 loci are involved:

L19- 4BBY1070

QUALITATIVE GENETICS AND MULTIFACTORIAL GENES

Calculating frequency of specific progeny in crosses with multiple loci: AaBbCc X AaBbCc yields 64 different genotypes Instead of drawing out a punnet square with the 64 possible progenies, this can be calculated by considering each locus separately

If the number of F2 individuals resembling either of the two extreme phenotypes can be determined, the number of loci n (polygenes) is calculated as: E.g. if the ratio of F2 individuals expressing either extreme phenotype is 1/64 then: 1/64 = n=3 Calculating number of polygenes for low numbers: (2n + 1) = number of distinct categories Solve for n 2n + 1 = 5 N=2 Assumptions made for both equations: a) All relevant alleles contribute equally b) Phenotypic expression is not affected significantly by environmental factors For many quantitative traits, these assumptions may not be true. So, when studying organisms’ large numbers should be studied. The study of polygenic traits relies on statistical analysis - Polygenic traits are usually measured in a sample of individuals that is large and representative of the population from which it is drawn. - The data often form a normal distribution that is a characteristic bellshaped curve when plotted as a frequency histogram - Variance provides information about the spread of data around the mean. - The mean can be misleading, as two sets of sample measurements for a quantitative trait can have the same mean but different distribution of variances around it.

Variance

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QUALITATIVE GENETICS AND MULTIFACTORIAL GENES

Correlation coefficient (r) between the two characters can be calculated to figure out what extent does one phenotypic character influence another. r ranges from -1 to +1. + Values means an increase in one trait is Correlation associated with an increase in the other. coefficient (r) Heritability: how much of the observed phenotypic variation is due to genotype differences between individuals for multifactorial traits? A value approaching 1 indicates that environment has little impact (trait mostly controlled by genotype). A value approaching 0 indicates that genotype has little impact (trait mostly controlled by environment).

Method for estimating heritability used by animal and plant breeders: -

Variation among members of the same inbred strain reared under different conditions is predominantly due to environmental factors. Variation between different inbred strains reared in a constant environment is predominantly due to genetic factors. This type of experimental analysis not possible for assessing heritability of human traits!

Twin studies allow an estimation of heritability in humans. Monozygotic (identical) twins: derived from a single zygote that divides mitotically and then splits into two separate cells, giving rise to genetically identical embryos. Dizygotic (nonidentical/ fraternal) twins: derived from two different zygotes (50% genetic identity). -

For a given trait, phenotypic differences between monozygotic twins (MZ) are equivalent to environmental variance (because genotype variance is zero) Phenotypic differences between dizygotic twins (DZ) are equivalent to environmental and genetic variance.

Comparing extent of phenotypic variance for the same trait between MZ and DZ pairs provides an estimate of heritability. o Twins are concordant for a trait if they both express it. o They are discordant if one expresses it and the other does not. Concordance in MZ twins > DZ twins, is evidence for a strong genetic component controlling the trait ABO, eye colour and hair colour controlled by genes. Therefore, only affects DZ.

Concordance particularly useful in assessing heritability of complex disorders in humans.

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QUALITATIVE GENETICS AND MULTIFACTORIAL GENES

A strong heritable component for all the above (apart from sporadic cancer)

Twin studies have limitations: MZ twins may be identical early in development, but after the split into two distinct embryos, genotypes can diverge slightly. - Copy number variation (CNV) can appear- bits of genome deleted or duplicated in 1 twin. In one e.g. a CNV difference in an MZ pair was associated with chronic lymphocytic leukaemia in one twin, but not the other. - Gene expression patterns change with age due to covalent modification of DNA and histones. Could explain some cases of MZ twin discordance Combination of genetic and environmental contribution gives rise to the threshold model

Liability of an individual to develop a given disorder depends on combination of the number of predisposing genes, and exposure to environmental factors (principally diet, in the case of type II diabetes mellitus) How to identify the genes involved in a trait: During the pre-genomic era: Linkage analysis Linkage: The proximity of two or more markers on a chromosome. A statistical method for detecting linkage between a disease and markers of known location by following their inheritance in families. During the post genomic era: Genome Wide Association Studies (GWAS) Directly comparing the DNA sequence of individuals to establish if a variant in DNA sequence is associated with a trait (typically a disease, in this case). GWAS studies reveal most significant type of variation in human gene pool is the SNP (single nucleotide polymorphism). This is the single base pair changes between genomes of individuals and make up 90% of all human genetic variation. Many of these are contributory risk factors to diseases. Some SNPs have more affect than others such as one SNP in haemoglobin (in homozygous) is sufficient to cause sickle cell anaemia. Some SNP have a small effect and are harder to track down and thus we use GWAS to track them.

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QUALITATIVE GENETICS AND MULTIFACTORIAL GENES

GWAS example: GWAS applied to type II diabetes reveals that 65 genetic polymorphisms that are associated with T2D. These variants have a small association and it is their combined effect that causes T2D. Identifying the SNPs will allow to identify the genes which will help identify the protein. This is helpful in understanding the biology of the disease and contributes towards strategies designed to control it via pharmaceutical intervention. -

A polymorphism in KCNJ11 is one of the genetic variants associated with type II diabetes.

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KCNJ11 is a potassium channel

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A mutation in this channel decreases responsiveness to glucose decreases insulin secretion.

Role of K+ in secreting insulin: 1. Glucose taken up by the GLUT2 transporter. 2. Glycolytic phosphorylation produces ATP so ATP:ADP ratio rises. 3. High ATP:ADP inactivates the ATP sensitive potassium channel and inhibits K+ efflux. 4. High intracellular charge causes Ca++ influx. 5. Ca++ influx causes exocytic release of insulin from storage granules. SNP can be used in forensic studies: -

PCR done on SNP to amplify it.

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Analysis of the SNPs in 6 genes allows prediction of eye colour from DNA left at crime scene....