What favorite organism of geneticists is described in the right-hand column?

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1 What favorite organism of geneticists is described in the right-hand column? Model Organism fruit fly?? Generation time 12 days ~ 5000 days Size 2 mm mm Brood size hundreds a couple dozen would be remarkable Cool phenotypic variation? Yes Yes Easy to work with? Yes Varies; sometimes uncooperative 1

2 Humans as a model for [higher?] eukaryotes.. Explore human genetics with OMIM Online Mendelian Inheritance in Man 2

3 Biol 321 Guidelines for Interpreting Human Pedigrees Affected means that the person has the trait or phenotype being analyzed. Some rules apply only to rare traits, that is traits that occur infrequently in the population under examination. If a recessive allele is rare, assume that most unaffected individuals will not be carrying (that is, will not be heterozygous for) the allele. If a person is affected with a rare dominant trait, assume the person is heterozygous for the allele. Interpretation of pedigrees can be complicated by incomplete penetrance, variable expressivity, genetic heterogeneity, among other factors. For our purposes, we will assume that there are no complicating factors and unless evidence to the contrary is presented. Autosomal Recessive 1. trait appears in progeny of unaffected parents 2. the trait breeds true and both sexes are equally affected 3. some degree of inbreeding may be present (rare trait) Autosomal Dominant 1. affected offspring have at least one affected parent 2. trait is passed directly from affected individual to affected individual 3. two affected individuals may have an unaffected child (that is, the trait may not breed true) 4. both sexes are equally affected X-linked Recessive 1. all daughters of affected males are carriers; all sons of affected females are affected 2. affected female will have an affected father 3. the phenotype skips from father to grandson 4. phenotypic expression is higher in males than in females X-linked Dominant 1. affected males produce all affected daughters and no affected sons 2. a heterozygous female will transmit the trait to about 1/2 of her sons and about 1/2 of her daughters 3

4 Meet Izzy and her brother Aiden 50-60% of congenital deafness is genetic Even though the action of many different genes is essential to normal hearing, inherited deafness is a monogenic trait This means that mutations in just one of the genes required for normal hearing can result in a total hearing loss The most common cause of hearing loss in American and European populations is a mutation in the connexin 26 (Cx26) gene. Cx26 has a carrier rate of 3%, similar to that for cystic fibrosis, and it causes about 20% of childhood deafness. 4

5 How Genes are Named: Functional Role Note that connexin 26 is not named for its mutant phenotype but rather its name reflects its role in gap junction formation more about the connexin 26 gene (located on chromosome 13): 5

6 The KE family is a great example of phenotypic variation indicating the existence of a previously unknown gene Transmission pattern of a severe speech and language disorder in the KE family The gene defined by this phenotypic variation is called FOXP2 This gene is important for normal speech and may have been important in the evolution of that quintessential human trait: speech These individuals have difficulties making movements of the mouth and larnyx which are necessary for normal articulation. They have deficits in language processing and grammatical skills but have normal non-verbal IQ. *Ignore asterisks in this pedigree 6

7 How Genes are Named: Acronyms Note that the FOX P2 gene is not named for its mutant phenotype. FOX P2 is an acronym that referred to the molecular function of the gene product: forkhead box P2 a type of transcription factor. Guess where the name forkhead* came from? The story of FOX P2 Gene variation may explain speechless apes FOX P2 protein contacting DNA *YES! You guessed correctly. forkhead is a gene name bestowed by a Drosophila geneticist on a gene whose mutant phenotype involves bizarre spiked-head structures in fruitfly embryos 7

8 Ì What mode(s) of inheritance is(are) consistent with the pedigree? Ì Is there some aspect of the pedigree that excludes a specific mode of inheritance? è Failure to breed true excludes recessive inheritance (assuming no complications) è If a female has the trait and the father does not, then the trait cannot be X-linked recessive è Can you think of similar rules for X-linked dominant inheritance We will focus on issues that arise in pedigree analysis that are not necessarily of concern when working with model organisms such as: how the frequency of a trait in the population under study might influence the interpretation of pedigree data small sample sizes and ratios that are not informative 8

9 Examine the following pedigree carefully. Copies of this pedigree will be distributed in class. assuming the trait (filled in symbols) is very common in the general population, what mode or modes of inheritance are consistent with the data assuming the trait (filled in symbols) is very rare in the general population, what mode or modes of inheritance are consistent with the data 9

10 The frequency of a genetically determined trait will depend on the genetic composition of the population allele frequency: the proportion of all copies of a gene in a specific population that are of a given allele type **The Frequency of inherited disorders database compare cystic fibrosis and retinoblastoma and cystinuria ALSO: look at PROBLEM 12 in assignment set 1 again 10

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12 Cystinuria (pedigrees follow) Mutations in the SLC3A1 and SLC7A9 genes cause cystinuria. The SLC3A1 and SLC7A9 genes code for subunits of a transporter protein that is made primarily in the kidneys. A mutation in either one of these genes results in a dysfunctioning transporter protein-- preventing proper reabsorption of basic, or positively charged amino acids such as histidine, lysine, ornithine, arginine and cysteine. NOTE: cystinuria is a single gene trait because a mutation in either of these genes will result in cystinuria How Genes are Named: Acronyms SLC3A1 = solute carrier family 3 (amino acid transporter) member 1 12

13 Examine pedigree 170: what modes of inheritance are consistent with this pedigree? What do the double parallel lines connecting some parental units indicate? OVERALL: Taking all of the pedigrees together, what is the mode of inheritance of this trait? 13

14 The frequency of cystinuria in the UK is about 1/20,000 (one affected individual per 20,000 people). In contrast the frequency of cystic fibrosis (common AR disease state) is 1/2500 with a carrier frequency of ~1/50 Carrier frequency for a connexin-26 mutation is also ~1/50 (averaged over 17 European countries) What is the relevance of this info to these pedigrees? 14

15 In general: the rarer a recessive disease state, the more likely it is that an affected individual is the product of inbreeding (typically a mating between first cousins) Figure pg 653 of text Frequency of first cousin marriages for parents of children showing several recessive disorders compared to first cousin marriages for families in general. In Japan, about 5% of marriages are between first cousins; however, the proportion of families with children having microcephaly is over 75%, a 15-fold increase Are first cousin marriages legal in the US? 15

16 Update on the genetics risks of first cousin marriages Where cousins can marry in the USA Beyond Kissing Cousins - Marriage Taboos Erode 16

17 Examine pedigrees 301 & 172: are these pedigrees inconsistent with AR inheritance? What is the probability of each of these outcomes? 17

18 Examine pedigree 150: what is the probability of that particular sibship (first 3 progeny are unaffected and the fourth affected)? Overall, how often do you expect to see this 3:1 ratio (dominant: recessive) from two het parents? If all of the data from het parents are pooled, do you see a clean 3:1 ratio? If not, can you explain the bias in the data? 18

19 What is the overall probability of two hets producing: 1 affected and three unaffected progeny? For this calculation, you need to figure out the possible scenerios consistent with 3 dominant and 1 recessive progeny all affected? all unaffected? three affected and one unaffected two affected and two unaffected (1 - all other possibilties) This analysis of expected frequencies given a small sample sizes illustrates how the progeny ratios will bounce around if only a small number of progeny are examined 19

20 What is the overall probability of two hets producing: 1 affected and three unaffected progeny? For this calculation, you need to figure out the possible scenerios consistent with 3 dominant and 1 recessive progeny all affected? all unaffected? three affected and one unaffected two affected and two unaffected (1 - all other possibilties) This analysis of expected frequencies given a small sample sizes illustrates how the progeny ratios will bounce around if only a small number of progeny are examined 1/4 3/4 3/4 3/4 20

21 Rexamine data on pg 11 Presumably with a collection of pedigrees and a large enough set of data, the segregation patterns (ratios) will tend to approximate predicted probabilities. But, if all the data are combined (looking at progeny of heterozygous parents only), the ratio of normal to affected (wildtype to mutant) is closer to _?? to 1 rather than 3:1 Speculate about why the data might still be skewed even when a very large pool of data are assessed 21