Genetics Exam 2

Autosomal recessive diseases common in specific ethnic populations

- Sickle cell disease (Africans/African-Americans) - Tay-Sachs disease (Northern European Jews) - Thalassemias (South East Asians)

Cells have ___ copies of the alpha-globin genes (Alpha Globin Gene Cluster)

four (two on each homologous chromosome 16)

_____ has alanine as residue 136 (Beta Globin Gene Cluster)

gamma-A

_____ has glycine as residue 136 (Beta Globin Gene Cluster)

gamma-G

The gene_____ is the only gene in which mutations are known to cause oculocutaneous albinism type 1

TYR

CF: CFTR Gene codes for _________ protein or CFTR protein

transmembrane conductance regulator

What is rarer: affected individuals or carriers? (A.R)

Affected individuals

Sickle cell disease

(Africans/African-Americans)

Tay-Sachs disease

(Northern European Jews)

Thalassemias

(South East Asians)

The Chromosomal Location (A.R)

- Autosomal Chromosomes: 1 -22 Chromosomes - Sex Chromosomes: X & Y -Mitochondrial

The Phenotype (A.R)

- Dominant (Expressed when even only one chromosome carries the mutant allele.) - Recessive (Expressed only when both chromosomes of pair carry a variant allele)

Principle of Segregation

- Genes remain intact & distinct - Each parent gives one of pair of genes

Single Gene Disorders

-Mutation in a Single Gene -Inherited in Mendelian Manner

CF: Frequency of carriers in Caucasians

1/25

On average, the recurrence risk to the unborn sibling of the parents

1/4

The recurrence risk at each birth for an affected child is ___ in __ (2 carriers mating).

1/4

BETA GLOBIN GENE CLUSTER Chromosome?

11

gamma-G has glycine as residue_____ (Beta Globin Gene Cluster)

136

About _(#)_ ______ disorders phenotypes included in common adult diseases

200 Mendelian disorders

Hb is composed of ___ subunits

4

delta F508 is a deletion of _____ at position _____

A deletion of Phe (Phenylalanine) at position 508

penetrance

Affected individuals always express clinical phenotype if they have two copies of the mutant gene

For Two Carriers Mating: At each birth, there is the SAME recurrent risk of having:

An affected child: 1⁄4 or 25% A heterozygous child: 1⁄2 or 50% A genotypic normal child: 1⁄4 or 25%

____ numbers to identify individuals. Each generation starts with 1

Arabic

Pattern of Inheritance (single gene disorder)

Chromosomal location Phenotype (clinical expression)

ALPHA GLOBIN GENE CLUSTER: Chromosome?

Chromosome 16

Alpha 1 and Alpha 2 genes provide alpha-globin chains that combine with?

Beta-Globin chains

Most COMMON, severe, autosomal recessive disease among Caucasians

CF

CF caused by mutationS in the _____ gene

CFTR

Consanguinity is NOT true for

COMMON A.R diseases (cystic fibrosis, etc)

Heterozygotes or carriers of autosomal recessive diseases (do/do not) typically have clinical symptoms

Do NOT typically have clinical symptoms

Chromososome Disorders

Excess or Deficiency of Whole Chromosomes or Chromosome Segments

Principle of Independent Assortment

Genes at different loci are transmitted independently Not true for linked genes

Most common genetic diseases in the world

HEMOGLOBINOPATHIES

People who marry into the family are usually assumed NOT to be

HET or affected

Heterozygotes or carriers of autosomal recessive diseases have one _____ allele and one _____-______ allele

Have one mutant allele and one wild-type allele

Affected individuals with autosomal recessive disease have ___ mutant alleles

Have two mutant alleles

By three months of age, almost all Hb is

HbA

constitutes ~70% of total Hb at birth

HbF

the predominant Hb throughout fetal life

HbF

More common: Heterozygotes/carriers or affected homozygotes (A.R)

Heterozygotes/carriers more common than affected homozygotes

Incidence of serious single gene disorders higher in general population or hospitalized children?

Hospitalized children

Multifactorial Disorders

Interaction of Genetic and Environmental factors

DNA sequences in front of gene clusters that are involved in gene regulation are called

Locus Control Regions (LCRs)

REGULATION OF Hb SYNTHESIS is by

THE LOCUS CONTROL REGION (LCR)

MENDEL'S PRINCIPLES

Principle of Segregation + Principle of Independent Assortment

Consanguinity is more frequently found in the parents of patients with _______ genetic diseases

RARE A.R

Genes in the alpha and beta hemoglobin gene clusters are in the order that

they are expressed during development

An autosomal recessive phenotype, typically is seen only in the _______ of the proband, not in parents, offspring, or other relatives.

SIBLINGS

3 types of diseases caused wholly or partly by genetic factors

Single Gene Disorders Chromosome Disorders Multifactorial Disorders

New mutations in autosomal recessive disorders are rare (T/F)

T

Autosomal recessive: New mutations rarely detected clinically T/F

True

Hb is composed of 2 __ chains and 2 ___ subunits

Two alpha-like chains and two beta-like subunits

2 EXAMPLES OF AUTOSOMAL RECESSIVE DISEASES

Type 1 Albinism CF

Single gene disorders can also be important in

adult common diseases (200 Mendelian disorders phenotypes)

gamma-A has _____ as residue 136 (Beta Globin Gene Cluster)

alanine

The alpha ___ and alpha ____ genes are identical in sequence (ALPHA GLOBIN GENE CLUSTER)

alpha 1 and alpha 2 genes

HbA: Chain composition? Fraction of Total Hb?

alpha2Beta2 90%

HbF is composed of

alpha2gamma2

HbA: symbol? Stage of Development?

aplha2beta2 Adult

Proband indicated by

arrow

HEMOGLOBINOPATHIES are inherited as

autosomal recessive

More common: autosomal recessive or dominant

autosomal recessive

Phenotypes are more uniform in diseases inherited as (autosomal recessive or dominant)

autosomal recessive

Affected individuals with autosomal recessive disease have ___ symptoms

clinical

Most characteristic symptom of CF

excessive production of thick, sticky mucus in the lungs' airways

The parents of the affected person may in some cases be______. (This is especially likely if the gene responsible for the condition is rare in the population.

consanguineous

The rarer the trait in the general population, the more likely a_______ mating is involved (A.R)

consanguineous

Double line=

consanguinity

Most common mutation in CFTR gene is ______

delta F508

________ accounts for ~70% of all CF mutations

delta F508

autosomal recessive onsets ____ in life

early

For most autosomal recessives, males and females are_____ likely to be affected

equally

More likely to be affected: males or females (Autosomal Rec.)

equally likely to be affected

DNA sequences in front of gene clusters are involved in

gene regulation

Roman numbers to identify

generations

The different polypeptides of Hb are synthesized from different

genes

Gamma-G has _____ as residue 136

glycine

Parents of affected child are called _______, have one copy of mutant gene and are asymptomatic. (A.R)

heterozygotes

diffusion across placenta is aided by the fact that fetal Hb (HbF) has a (higher/lower) affinity for O2 than does maternal HbA under physiological conditions -In red blood cells, with 2,3-BPG present in both maternal and fetal cells

higher

Type 1 Albinism symptoms include

hypopigmentation of the skin and hair (including brows and lashes)

The trait may appear as an _____ event in small sibships (A.R)

isolated (sporadic)

Genetic risk to offspring of consanguineous marriages is____ than thought

less (first cousins risk: 3-5%) (unrelated: 2-3%)

Principle of Independent Assortment is not true for

linked genes

Most autosomal recessive diseases are due to _____-of-____ mutation

loss-of-function mutations (Mutations reduce or eliminate the function of the gene product)

At birth, gamma chain synthesis is switched (on/off) (HbF)

off

Mostly disorders of the _______ age range (single gene inheritance)

pediatric

autosomal recessive often have complete ______

penetrance

A fetus obtains O2 by diffusion across

placenta

Depending on the developmental stage, the subunits of Hb are composed of different

polypeptide

Affected individuals with autosomal recessive disease have little to no _____ ______ coded for by mutant genes

protein function

Clinical symptoms of CF

respiratory and gastrointestinal problems and elevated sweat electrolyte concentrations

CF: cells lining the airway do not transport ___ and ____ normally, so mucus and other airway secretions may be depleted of water and becomes thick and sticky, breeding grounds for bacteria

salt and water

The clinical symptoms of A.R may be found in ______, but not parents of affected or the offspring of affected

siblings

If one parent is a carrier, affected offspring are rare because risk of new mutation by spontaneous ________ ranges from 1 in 105 to 1 in 106, much less than carrier frequency (1 in 20 to 1 in 1000)

spontaneous mutagenesis

Temporal switches of globin synthesis are accompanied by changes in

the major sites of synthesis

Cells have ___ copies of the beta-globin genes (Beta Globin Gene Cluster)

two (one on each homologous chromosome 11)

HbF is ___%of total Hb in adults

~1%

Heterozygotes or carriers of autosomal recessive diseases usually have _____ of normal protein function

~50%