Genetics Spring 2015

Transmission Genetics: The Principles of Segregation

Outline

Pisum sativumThe study of inheritance of traits or Transmission Genetics is also called Mendelian Genetics because it follows the principles first defined by Mendel (Exceptions to the rules ….)

Gregor Mendel grew more than 33,500 pea plants over a period of eight years, including more than 6400 plants in one year alone.

Morphological and Molecular Phenotypes

The seven traits in garden peaPisum sativum

studied by Mendel

Molecular basis of wrinkled seed mutationThe wildtype allele W is dominant to the mutant allele w, which contains an insertion of foreign DNA (allele vs. phenotype codominance …… CONFUSING)

(A) W (round) is an allele of a gene that specifies the amino acid sequence of starch branching enzyme I (SBEI). (B) w (wrinkled) is an allele that encodes an inactive form of the enzyme because its DNA sequence is interrupted by the insertion of a transposable element. (C) At the level of the morphological phenotype, W is dominant to w: Genotypes WW and Ww have round seeds, whereas genotype ww has wrinkled seeds.

Heterozygosity in the F1 leads to a 3:1 ratio in the F2

P = parental WW x ww

F1 = all Ww

F2 = 1 WW + 2 Ww + 1 ww

Genetic explanation of dominance in F1 and 3:1 segregation in the F2

Segregation of a Single Gene

Punnett Square provides graphical calculations of gametes and progeny

Key features of single gene inheritance• Genes come in pairs: each cell has two alleles of a

gene.• For each pair of genes, the alleles may be the same or

different (homozygous [WW or ww] or heterozygous [Ww]).

• Each gamete contains only one allele of each gene.• Union of male and female gametes is random and

reunites alleles in pairs.• Reciprocal crosses gave same results (male x female)

because all traits are not sex-linked in this case (different form lab experiments).

In the formation of gametes, the paired hereditary determinants separate (segregate) in such a

way that each gamete is equally likely to contain either member of

the pair.

Mendel’s first law:The Principle of Segregation

Phenotypes of the progeny reveal relative frequencies of the different gametes produced by heterozygous parents. The recessive parent contributes only recessive alleles.

Testcross (cross between heterozygote and homozygous recessive) or more generally backcross (cross between heterozygote and one of the parental genotypes) allow the verification of the Principle of Segregation.

Segregation of Two or More GenesDihybrid cross: Independent assortment gives rise to the F2 9:3:3:1 phenotype ratio

Independent segregation of the W, w and G, g allele pairs means that among each of the W and w gametic classes, the ratio of G : g is 1 : 1

Genotypes and phenotypes resulting from a testcross of the Ww Gg double heterozygote.

Mendel’s second law:The Principle of Independent

AssortmentSegregation of the members of any pair of alleles is independent of the segregation of other pairs in the formation of gametes (For genes on different chromosomes, or unlinked).

Human Pedigree Analysis - Conventional SymbolsA pedigree is a diagram of family tree showing phenotypes, sexes and relationships of individuals in multiple generations.

The proband is the individual being studied (propositus or index case)

The consultand is the person who brings the family to attention by consulting a geneticist.

Important features to consider when analyzing a pedigree

• Large deviations from expected ratios are observed, because of the relatively small number of progeny.

• Look at several generations of offspring to see segregation of trait to assess whether a particular trait is dominant or recessive.

• If a trait appears to be inherited in Mendelian fashion, then conclude it is due to a single gene.

Relationship within a kindred

Mendelian Inheritance – Factors affecting inheritance

•A genotype can be homozygous, heterozygous, compound heterozygous or hemizygous.

•Syntenic genes (the presence on the same chromosome of two or more genes that may or may not be transmitted as a linkage group but that appear to be able to undergo independent assortment during meiosis) differ from linked genes.

Crosses indicate disease-causing mutations; boxes, alleles. Epidermolysis bullosa simplex

•The phenotype of a disorder is either dominant, co-dominant or recessive and involved either autosomes or sex-chromosome. In addition, some disorders are linked to mitochondrial DNA.

•Most recessive disorders are due to loss-of-function mutations.

•Pure dominant disorders are rare (co-dominance and semi-dominance).

Hair-nail ectodermal dysplasia

Huntington Disease

Difference in phenotypic expression can be explained by the following:Penetrance (all-or-none): percentage of individual with a predisposing genotype who are affected (population).Expressivity (more-or-less): severity of the phenotype (individual).Pleiotropy: one allele responsible of several phenotypes. Age of onset, other genes and environmental factors.

2

3

1

For each of the scenarios (1 to 3), where each circle represents an

individual, tell if the population shows either variable expressivity, variable

penetrance, both or none (each individual has the susceptible

genotype).

Human Pedigree Analysis – Autosomal Dominant Inheritance•Seen in homozygous dominant or heterozygous individuals and form half of Mendelian disorders.•Diseased individuals are present in every generation (indicates dominant disease): affected offspring have one affected parent.•Males and females are both about equally affected (indicates autosomal inheritance).•About half of individuals in sibships with affected parent have disease.

Pedigree of a human family showing the inheritance of the dominant gene for Huntington disease (complete penetrance)

More than 99% of individuals with achondroplasia have one of two mutations in FGFR3. In about 98% of individuals, the mutation is a p.Gly380Arg substitution, resulting from a G-to-A point mutation at nucleotide 1138 of FGFR3.

Slip-hand deformity

Failure of penetrance

leads to apparent

skipping of generations,

thus complicating

genetic counseling.

Failure of penetrance

leads to apparent

skipping of generations,

thus complicating

genetic counseling.

Neurofibromin is a tumor suppressor protein encoded by the Nf1 gene on human chromosome 17. Neurofibromin helps protect cells against cancer by suppressing Ras, a potent activator of cell growth and proliferation. People with mutations in the Nf1 gene develop neurofibromatosis type I (NF1), a neurological disorder that affects 1 in 3,500 people world-wide.

Neurofibromatosis, type I (NF1)

Is failure of penetrance or new mutation or variable expressivity responsible for the

proband’s phenotype (all susceptible adults display a phenotype)?

Human Pedigree Analysis – Autosomal Recessive Inheritance•Seen in homozygous recessive or compound heterozygous individuals.•Females and males are equally likely to be affected.•Affected individuals, if they reproduce (with normal person), usually have unaffected progeny.•Mating of two heterozygotes (at least) is required to produce an affected (homozygous recessive) child.•Most affected individuals have unaffected parents.•The parents of affected individuals are often relatives.

Pedigree of a human family showing the inheritance of the recessive gene for Albinism disease

•If mutant alleles are common in the general population (such as mutated CFTR), then the autosomal recessive disorders are not impacted by consanguinity.•If mutant alleles are rare, then the frequency of autosomal disorders increases with consanguinity.•Xeroderma pigmentosum is a genetically heterogeneous autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age.•The excision repair mechanism, involved in DNA repair is impaired, due to mutations in the gene encoding XP genes.

Xeroderma pigmentosum

Molecular markers aid pedigree analysisThere is no masking of one allele by another allele for DNA markers (codominance of alleles is seen)

Human pedigree and gel showing segregation of SSRP alleles (microsatellites)

•New mutations can arise, thus starting a new diseased phenotype in a family.

•Fitness of zero (genetic lethal) for the disorder means that the individual does not reproduce (genetic lethal disorder) as opposed higher fitness .

Incomplete Dominance and Epistasis

Red versus white flower color in snapdragons shows incomplete dominance in pigment production

Incomplete dominance - Snapdragons

Yields a 1:2:1 phenotypic ratio in the F2

Compare with normal phenotype ratio observed in the F2 is 3:1 for a simple dominant/recessive allele pair

Incomplete Dominance - Human Blood Group ABO

Multiple alleles for blood group antigensEach person only has two

Epistasis - Labrador

Review Problem

s

1. Write the genotype of each individual above his/her symbol2. What is the most-likely mode of inheritance of the affected

phenotype? Explain

James, a 3-week-old infant with ectrodactyly (a rare malformation of the hands and feet) is brought to you by his parents, Steve and Sonya. James has one older sibling who has normal hands and feet. Although neither parent has hand or foot abnormalities, members of Steve’s family are affected with ectrodactyly. A family history reveals the following pedigree, where symbols representing individuals affected with ectrodactyly are shaded and symbols representing individuals with no clinical symptoms are not shaded.

What mode of inheritance is most suggested by this pedigree?