Michael R. Cummings

David Reisman • University of South Carolina

Pedigree Analysis in Human Genetics

Chapter 4

Fig. 3-16, p. 60

Male Aborted or stillborn offspring

FemaleDeceased offspring

Mating

Mating between relatives (consanguineous) or Unaffected individual

I Parents and children. Roman numerals symbolize generations. Arabic numbers symbolize birth order within generation (boy, girl, boy)

or Affected individual

II or1 2 3

Proband; first case in family that was identified

P PMonozygotic twins or Known heterozygotes

Carrier of X-linked recessive traitDizygotic twins

Offspring of unknown sex Infertility

Human Pedigrees

Ancestry.com—beware this can be addictive!

Patterns of Inheritance

Patterns in the pedigree are used to determine how a trait is inherited• Autosomal dominant• Autosomal recessive• X-linked dominant• X-linked recessive• Y-linked• Mitochondrial inheritance

4.2 Autosomal Recessive Traits

Characteristics of autosomal recessive traits• For rare traits, most affected individuals have

unaffected parents• All children of affected parents are affected• The risk of an affected child with heterozygous

parents is 25%• The trait is expressed in both males and females

4.2 Autosomal Recessive Pedigree

Example of an Autosomal Recessive Trait : Cystic Fibrosis Cystic fibrosis: A fatal recessive genetic disorder

associated with abnormal secretions of the exocrine glands

1 in 25 Americans of European descent 1 in 46 Americans of Hispanic descent 1 in 65 African Americans 1 in 250 Asian Americans

Cystic Fibrosis Gene Product (CTRF)

The CFTR gene was identified in 1989 CFTR protein controls the movement of chloride ions

across the plasma membrane Water moves from the outside of the cell to the

inside In lung cells, this makes the mucus very thick

Exploring Genetics::

Noah’s “flesh was white as snow”• From the Book of Enoch the Prophet

Phenotype: Lack of pigmentation Albinism is inherited as an autosomal recessive trait

From chapter 1—old paintings and historical texts described birth defects that were inherited

4.3 Autosomal Dominant Traits

Characteristics of autosomal dominant traits• Heterozygotes exhibit the phenotype• Every affected individual has at least one affected

parent (except in traits with high mutation rates) • Two affected individuals can have an unaffected child• Usually an affected family member in each generation

4.3 Autosomal Dominant Pedigree

Example of an Autosomal Dominant Trait: Marfan Syndrome Marfan syndrome• An autosomal dominant genetic disorder that

affects the skeletal system, cardiovascular system, and eyes

• Individuals are tall, thin, long arms and legs. Thin fingers

• Heart defects• Abraham Lincoln?????

4.4 Sex Linked Inheritance

Genes on sex chromosomes have a distinct pattern of inheritance

X-linked• When a gene for a particular trait is located on the X

chromosome

Y-linked• Pattern of inheritance that results from genes located

only on the Y chromosome

For sex-linked traits males are Hemizygous

Hemizygous• Refers to males when the gene for a trait is on the X-

or Y- chromosome.• Since males have just one X-chromosome, and one

Y-chromosome, they will express whatever allele is present—the recessive or dominant

Fig. 4-10, p. 79

X-Linked Dominant Traits

Quite rare inheritance pattern (only 3 known)

Affected males produce all affected daughters and no affected sons

A heterozygous affected female will transmit the trait to half of her children• Sons and daughters are equally affected

(e.g., vitamin D resistant rickets)

X-Linked Recessive Traits

X-linked recessive traits affect males more than females because males are hemizygous for genes on the X chromosome

Color blindness• Defective color vision caused by reduction or absence

of visual pigments• Three forms: red, green, and blue blindness• About 8% of the male population in the US affected

Testing For Color Blindness

People with normal color vision see the number 29 in the chart; those who are color-blind cannot see the number

Fig. 4-14, p. 81

X-linked recessive trait Punnett square

Pause the presentation and try to answer these questions.

A woman who is heterozygous for color-blindness is expecting a child. The father had normal vision. What is the probability that, if female, the child will be color-blind? What about the probability for a male child?

X-linked recessive trait Punnett square

XC

Xc

XC Y

XCXC XCY

XCXc XcY

Zero probability the baby, if female will be color-blind, but thereis a 50% chance she will be a carrier. And there is a 50% chance that, if male, he will be color-blind.

Example of an X-linked Recessive Trait: Muscular Dystrophy

Muscular dystrophy• A group of genetic diseases associated with

progressive degeneration of muscle tissue• Duchenne and Becker muscular dystrophy are

inherited as X-linked recessive traits• Duchenne muscular dystrophy (DMD) affects 1 in

3,500 males in the US

4.5 Paternal Inheritance: Y Chromosome

Only males have Y chromosomes• Genes on the Y chromosome are passed directly from

father to son

All Y-linked genes are expressed• Males are hemizygous for genes on the Y

chromosome

To date only 36 Y-linked traits have been identified

4.6 Non-Mendelian Maternal Inheritance: Mitochondrial Genes

Mitochondria • Cytoplasmic organelles that convert energy from food

into ATP (ATP powers cellular functions)• Have their own DNA that codes 37 mitochondrial

genes

Genetic disorders in mitochondrial DNA are associated with defects in energy conversion

Mitochondrial Inheritance

Mitochondria (and genetic disorders caused by mutations in mitochondrial genes) are maternally inherited

Mitochondria are transmitted from mothers to all their offspring through the cytoplasm of the egg

4.7 An Online Catalog of Human Genetic Traits OMIM• Genetic traits are described, cataloged, and

numbered in a database called Online Mendelian Inheritance in Man

• OMIM is updated daily and contains information about all known human genetic traits

• Each trait is assigned an OMIM number• There are more that 10,000 entries

• **Chapter 4 Web Assignment on OMIM (See the course site for week 2 assignments.)

Fig. 4-20, p. 86

4.8 Many Factors can Affect the Pattern of Inheritance

Variations in gene expression affect pedigree analysis and assignment of genotypes to members of the pedigree

Several factors can affect gene expression• Interactions with other genes• Interactions between genes and the environment

4.8 Many Factors can Affect the Pattern of Inheritance

Phenotypes are often age related (onset of symptoms occurs in adulthood)

• Example: Huntington disease

Penetrance and expressivity cause variations in phenotype

• Penetrance: the probability the the phenotype will appear• Expressivity: The range of phenotypes from a given

genotype

Penetrance and Expressivity

Baby Born In Bay Area With 12 Functioning Fingers, 12 ToesPosted: 6:07 pm PST January 30, 2009Updated: 2:25 pm PST November

13, 2009DALY CITY, Calif. -- A Daly City couple is beaming after becoming the proud

parents of a healthy but incredibly rare baby boy this month.Baby Kamani Hubbard has six-fully formed and functional fingers and toes

on his hands and feet. It's called "polydactyly" -- extra digits -- not an uncommon genetic trait, but Bay Area doctors say they've never seen a case so remarkable.

Born at San Francisco's Saint Luke's Hospital three weeks ago, Hubbarb seemed so perfect at birth no one noticed.

(Polydactyly is an autosomal dominant trait that was in the father’s family.)