The Chromosomal Basis of Inheritance

Drosophila melanogaster

!  Fruit fly •  Model organism for animal genetics •  Compared to Mendel’s peas •  Used to test linkage and recombination

Evidence for Gene Linkage

1. P generation

Wild-type female (red eyes, normal wings)

Double mutant male (purple eyes, vestigial wings)

prpr vgvg pr+pr+vg+vg+

X

pr+pr vg+vg

2. F1 generation

F1 dihybrid (red eyes, normal wings)

pr+pr vg+vg

F1 dihybrid (red eyes, normal wings)

pr+pr vg+vg

F1 dihybrid (red eyes, normal wings)

3. Testcross

Double mutant male (purple eyes, vestigial wings)

prpr vgvg

X

4. Progeny of testcross

Wild type (red, normal)

purple, vestigial

red, vestigial

purple, normal

Observed 1339

Expected, if assort independently

~710

Parental phenotypes

1195 151 154

Recombinant phenotypes

~710 ~710 ~710

= 2839 total progeny

(709.75 each) = 2839 total progeny

prpr vgvg pr+pr vgvg prpr vg+vg pr+pr vg+vg

Testcross parents

F1 dihybrid (red eyes,

normal wings)

Female gametes (ova)

Testcross progeny

Parental

Meiosis

Wild-type (red, normal)

1339

purple, vestigial

1195 Parental

Recombinant

Recombinant

red, vestigial

151

purple, normal

154

Double mutant (purple eyes,

vestigial wings)

Meiosis

Male gamete (sperm)

vg+ pr+

pr vg

pr vg

pr vg

Total progeny = 2839 Recombinants = 305 Parentals = 2534

Chromosome Maps

!  Recombination frequencies used to determine relative locations on a chromosome

!  Linkage map for genes a, b, and c:

!  1 map unit = 1% recombination = 1 centimorgan

Map: Drosophila Chromosome 2

4 2

Drosophila chromosomes

Y X

3 1

red eyes

aristaless (short aristae)

long wings

Wild-type phenotypes

gray body

red eyes

long wings

104.5 0 13.0 48.5 54.5 67.0

Mutant phenotypes

long aristae dumpy wings

black body

purple eyes

vestigial wings

brown eyes

Recombination Occurs Often

!  Widely separated linked genes often recombine •  Seem to assort

independently •  Detected by testing

linkage to genes between them

Sex Determination in Humans

The X-Y system

The X-0 system

The Z-W system

The haplo-diploid system

Parents

Sperm Ova

Zygotes (offspring)

Different systems of sex determination

Sex-linked Genes: Eye Color Phenotypes in Drosophila

!  Normal wild-type: red eye color !  Mutant: white eye color

White eyes P generation

Red eyes (wild type)

Red eyes F1 generation

Red eyes

F2 generation Sperm

Eggs

3/4 red eyes : 1/4 white eyes

All red-eyed females

1/2 red-eyed, 1/2 white-eyed

males

Y

Red eyes

P generation

White eyes

X X X

F1 generation

F2 generation Sperm

Eggs

White eyes Red eyes

1/2 red eyes : 1/2 white eyes

1/2 red-eyed, 1/2 white-eyed

females

1/2 red-eyed, 1/2 white-eyed

males

White eyes P generation

Red eyes (wild type)

Red eyes F1 generation

Red eyes

F2 generation Sperm

Eggs

3/4 red eyes : 1/4 white eyes

All red-eyed females

1/2 red-eyed, 1/2 white-eyed

males

Y

Red eyes

P generation

White eyes

X X X

F1 generation

F2 generation Sperm

Eggs

White eyes Red eyes

1/2 red eyes : 1/2 white eyes

1/2 red-eyed, 1/2 white-eyed

females

1/2 red-eyed, 1/2 white-eyed

males

Human Sex-Linked Genes: Inheritance of Hemophilia

!  In descendents of Queen Victoria of England

X Inactivation : Calico Cats

!  Heterozygote female (no male calico cats)

X Inactivation : Human Female

Affected skin with no normal sweat glands (In this tissue, the X chromosome with dominant allele has been condensed. The recessive allele on the other X chromosome is being transcribed.)

Unaffected skin (X chromosome with recessive allele was condensed; its allele is inactivated. The dominant allele on other X chromosome is being expressed in this tissue.)

Chromosomal Alterations (1)

!  Deletion: broken segment lost from chromosome

!  Duplication: broken segment inserted into homologous chromosome

Cri du Chat (Terminal Deletion Chromosome 5) Huntington’s Disease (Duplication)

Trinucleotide Repeats of CAG on chromosome 4 (4p16.3).

Dominant

Chromosomal Alterations (2)

!  Translocation: broken segment attached to nonhomologous chromosome

!  Inversion: broken segment reattached in reversed orientation

CML - Chronic Myeloid Leukemia (Reciprocal Translocation)

Down Syndrome (Trisomy 21) Nondisjunction (1)

!  Failure of homologous pair separation during Meiosis I

Nondisjunction (2)

!  Failure of chromatid separation during Meiosis II

Changes in Chromosome Number

!  Euploids •  Normal number of chromosomes

!  Aneuploids •  Extra or missing chromosomes

!  Polyploids •  Extra sets of chromosomes (triploids, tetraploids) •  Spindle fails during mitosis

Aneuploids

!  Abnormalities usually prevent embryo development

!  Exception in humans is Down syndrome •  Three copies of chromosome 21 (trisomy 21) •  Physical and learning difficulties •  Frequency of nondisjunction increases as women

age

Aneuploidy of Sex Chromosomes

Aneuploidy of Sex Chromosomes Klinefelter Syndrome (Trisomy XXY)

Turner Syndrome (Monosomy XO) Modes of Inheritance

!  Autosomal recessive inheritance

!  Autosomal dominant inheritance

!  X-linked recessive inheritance

Autosomal Recessive Inheritance

!  Males or females carry a recessive allele on an autosome

!  Heterozygote •  Carrier •  No symptoms

!  Homozygote recessive •  Shows symptoms of trait

Autosomal Recessive Inheritance

Autosomal Recessive Inheritance: Human Diseases

Cystic Fibrosis Albinism

Autosomal Dominant Inheritance

!  Dominant gene is carried on an autosome

!  Homozygote dominant or heterozygote •  Show symptoms of the trait

!  Homozygote recessive •  Normal

Autosomal Dominant Inheritance Autosomal Dominant Inheritance Progeria Achondroplasia

Polydactyly Syndactyly

X-Linked Recessive Inheritance

!  Recessive allele carried on X chromosome

!  Males •  Recessive allele on X chromosome •  Show symptoms

!  Females •  Heterozygous carriers, no symptoms •  Homozygous, show symptoms

X-Linked Recessive Inheritance

Genetic Counseling

!  Identification of parental genotypes •  Construction of family pedigrees •  Prenatal diagnosis

(including amniocentesis and chorionic villus sampling)

•  Postnatal genetic screening (Biochemical and molecular tests

!  Allows prospective parents to reach an informed decision about having a child or continuing a pregnancy

Early Detection and Diagnosis

Amniocentesis Chorionic villi sampling

Week 15-20 Week 10-12

Cytoplasmic Inheritance: Human Mutations in Mitochondrial Genes Genomic Imprinting

!  Expression of an allele is determined by the parent that contributed it •  Only one allele (from either father or mother) is

expressed

!  Other allele is turned off (silenced) •  Often, result of methylation of region adjacent to

gene responsible for trait

Genomic Imprinting: Prader-Willi and Angelman Syndrome

!  Specific partial deletion of chromosome 15 results in:

Angelman syndrome if it’s from the mother

Prader-Willi syndrome if the chromosome is from the father