Introduction to Genetics Lecture 1 Overview

Genetics for Statisticians MSc Course Duration: 18Hours, 6 x 3hour sessions Dates: Thursday 23 rd May: 4:30-8:15 Thursday 30 th May: 4:30-8:15 Thursday 6 th June: 4:30-8:15 Thursday 13 th June: 4:30-8:15 Thursday 20 th June: 4:30-8:15 Presenters: Dr Samuel Murray BSc, Hons, PhD, MRCP Dr Fotios Siannis PhD Session Titles: 1. Genetics: The basics 2. Analytical methodologies and global standardisation issues [measures, cutoffs, ROC, EQA, sens/spec, reproducibility and requirements] 3. Biomarkers and their surrogates: integration into clinical medicine [prog/pred, designs – old v new v novel, case control, Harvey W Equilb, endpoints-RR, cross over, censorship] 4. Practical application and interpretation of large data sets: ‘Omics’ [design, interpretation, validation, algorithms] 5. Spotting methodological flaws, limitations of study design, multiplicity [p53, OncoDx, missing data, understanding the question, MA, post hoc]

Impacts, Issues: The Color of Skin  Skin color comes from the pigment melanin Produced by melanocytes in skin cells More than 100 genes directly or indirectly influence amount of melanin in an individual’s skin Lead to many variations in skin color

Video: ABC News: All in the family: Mixed race twins

19.1 Basic Concepts of Heredity  Genes provide the instructions for all human traits, including physical features and how body parts function  Each person inherits a particular mix of maternal and paternal genes

Basic Concepts of Heredity (1)  Genes Humans have ~21,500 Chemical instructions for building proteins Locus: specific location on a chromosome  Diploid cells contain two copies of each gene on pairs of homologous chromosomes  Allele: each version of a gene

A Few Basic Genetic Terms

Many Genetic Traits Have Dominant and Recessive Forms

Basic Concepts of Heredity (2)  Homozygous condition: identical alleles  Heterozygous condition: different alleles  Dominant allele Effect masks recessive allele paired with it

Basic Concepts of Heredity (3)  Genetic representations Homozygous dominant (AA) Homozygous recessive (aa) Heterozygous (Aa)  Genotype Inherited alleles  Phenotype Observable functional or physical traits

Genotype and Phenotype Compared

19.2 One Chromosome, One Copy of a Gene  We inherit pairs of a genes (alleles) on pairs of chromosomes, but a gamete receives only one gene from each pair

One Chromosome, One Copy of a Gene  Monohybrid cross Learn more about genotypes  Segregation Pairs of alleles separated during gamete formation

The Trait Called a Chin Fissure Arises from One Allele of a Gene

Animation: Chromosome segregation

Each Pair of Gene Alleles Is Separated and Two Alleles End Up in Different Gametes

19.3 Genetic Tools: Testcrosses and Probability  When potential parents are concerned about passing a harmful trait to a child, genetic counselors must try to predict the likely outcome of the mating

Probability  Measure of the chance that some particular outcome will occur  Factor in the inheritance of single-gene traits  Cross CC x cc All of the offspring will be heterozygous, Cc  Cross Cc x Cc ¼ CC, ½ Cc, and ¼ cc

A Punnett Square Can Be Used to Predict the Result of a Genetic Cross  Punnett square Grid used to determine possible outcomes of genetic crosses Rules of probability apply because fertilization is a chance event Possibility can be expressed mathematically, e.g., between 0% and 100%  Most probable outcome does not have to occur  In a given situation, probability does not change

Making a Punnett Square Is One Way to Determine Likely Outcome of Genetic Cross

Different Genetic Results Possible in Second Generation after Monohybrid Mating

Use Multiplication to Figure the Probability of the Inheritance of Alleles

A Testcross Also Can Reveal Genotypes  Testcross Learn the genotype of a (nonhuman) organism Cross organism with homozygous recessive organism (aa) If all offspring are Aa, parent was probably AA If some of the offspring have the dominant trait and some have the recessive trait, parent was Aa

19.4 How Genes for Different Traits Are Sorted into Gametes  When we consider more than one trait, we see that the gene for each trait is inherited independently of the gene of other traits

How Genes for Different Traits Are Sorted into Gametes  Independent assortment Occurs during meiosis A given chromosome and its genes move randomly into gametes Metaphase I Metaphase II  Crosses between individuals heterozygous for two traits yields sixteen different gamete unions Probability displayed using a Punnett square

Independent Assortment: Chromosomes Moved at Random into Forming Gametes

Fig. 19-8, p. 378 One of two possible alignmentsThe only other possible alignment a Initial chromo- some alignments (at metaphase I): b The resulting alignments at metaphase II: c Possible combinations of alleles in gametes: ABabAbaB Stepped Art

Tracking Two Traits Shows the Results of Independent Assortment

Fig. 19-9, p. 379 CcDd meiosis, gamete formation meiosis, gamete formation 1/4 CD 1/4 Cd 1/4 cD 1/4 cd 1/4 CD 1/16 CCDD 1/16 CCDd 1/16 CcDD 1/16 CcDd 1/4 Cd 1/16 CCDd 1/16 CCdd 1/16 CcDd 1/16 Ccdd 1/4 cD 1/16 CcDD 1/16 CcDd 1/16 ccDD 1/16 ccDd 1/4 cd 1/16 CcDd 1/16 Ccdd 1/16 ccDd 1/16 ccdd Adding up the combinations possible: 9/16 or 9 chin fissure, dimples 3/16 or 3 chin fissure, no dimples 3/16 or 3 smooth chin, dimples 1/16 or 1 smooth chin, no dimples

Probability Rules Apply to Independent Assortment

19.5 Single Genes, Varying Effects  Some traits have clearly dominant and recessive forms  For most traits, however, the story is not so simple

One Gene May Affect Several Traits  Pleiotropy Wide-ranging effect of one gene  Sickle-cell anemia One amino acid substitution in hemoglobin Val instead of glu Pleiotropic effects Treatments

Single Genetic Change Leads to Many Physical Effects of Sickle-Cell Anemia

Fig a, p. 380

Fig b, p. 380

In Codominance, More Than One Allele of a Gene Is Expressed  Codominance Heterozygous for a trait, but both alleles are expressed Example: alleles for blood type determine presence or absence of polysaccharides on surface of red blood cells IA and IB; codominant when paired with each other  Multiple allele system A gene that has three or more alleles

There Are Several Possible Allele Combinations for ABO Blood Types

19.6 Other Gene Effects and Interactions  Many phenotypes, such as eye color, can’t be predicted with certainty  Biologists have uncovered several underlying causes for these variations

Other Gene Effects and Interactions  Penetrance Probability that someone who inherits an allele will have the phenotype associated with it  Cystic fibrosis Homozygous recessive 100% penetrant  Polydactyly Dominant allele for extra digits Incompletely penetrant

People with Polydactyly Have Extra Digits on Their Hands or Feet

Polygenic Traits Come from Several Genes Combined (1)  Polygenic traits Combined expression of several genes Skin and eye color; many variations due to the amount and distribution of melanin  Continuous variation Populations show a range of continuous differences Most evident in traits that can be measured, e.g., height

Polygenic Traits Come from Several Genes Combined (2)  Multifactorial trait Phenotypes shaped by more than one gene and affected by the environment, e.g., height

Eye Color Is Just One of Many Human Polygenic Traits

The Environment Can Affect Phenotypes  Height Diet low in protein Disease or injury that prevents the normal release of growth hormone  Skin color Tanning  Good lifestyle choices May limit the chances that a harmful gene(s) will be expressed

“Tongue-Roller” Trait Is Due to a Dominant Allele