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Single Gene Disorders Mendelian Inheritance • History – Gregor Mendel (1822-1884) studied traits of garden pea plants • All of the published information indicated that each trait that Mendel studied was determined by a single factor • The concepts of DNA, genes and chromosomes as we currently understand them were not known.

Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

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Page 1: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Single Gene DisordersMendelian Inheritance

• History– Gregor Mendel (1822-1884) studied traits

of garden pea plants• All of the published information indicated that

each trait that Mendel studied was determined by a single factor

• The concepts of DNA, genes and chromosomes as we currently understand them were not known.

Page 2: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Alleles

• alternative variants of genetic information (at a given locus)(of a gene)

• locus = a physical position on a chromosome• gene = a sequence of nucleotides which,

when transcribed produce a biologically active nucleic acid (almost always single stranded RNA)

• The prevailing version of an allele is the wild-type (normal) allele

Page 3: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Alleles 2

• Mutation: may be used to describe a new genetic change or may be used to indicate a disease-causing allele

• Once a wild-type allele is defined, all other alleles are mutant– exception polymorphic alleles

• Polymorphism = ‘many forms’– Arbitrarily defined if there is an alternative allele of a

frequency greater than 0.02– More precisely defined under terms of genetic

selection in a later lecture.

Page 4: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

More Definitions

• Genotype: the set of alleles which make up an individuals genetic constitution. May be used to describe the sum of all alleles (all genes) or be used to describe the set of alleles for a given gene or locus

• Phenotype: the observable expression of a genotype– may be a biochemical, morphological,

physiological, clinical or molecular trait

Page 5: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Single Gene Disorder• A phenotype produced by alleles of a single

locus which is abnormal.• A phenotype may be the result of one or two

mutant alleles• If the two alleles at a locus are identical to

each other, the individual is homozygous.– This term applies regardless of the alleles being

normal, mutant or polymorphic forms.– If the two alleles are different, the individual is

heterozygous.• If one of the two alleles in a heterozygote is the wild-type

allele, the term ‘carrier’ can be used.

Page 6: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

• If the two alleles are both mutant, but different from each other, the individual is said to be a compound heterozygote.

• If there is no second allele at a locus in a normal individual, that person is hemizygous– The obvious situations are the human X and Y

chromosomes in a chromosomally normal male. The DNA sequences are represented by one copy.

Page 7: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Dominant and Recessive

• Defined at the level of the phenotype• Classically, any phenotype expressed in both

the homozygote and heterozygote states was said to be dominant.– A phenotype only expressed in a homozygote

state is recessive

• Practically, any phenotype expressed in heterozygotes is dominant – even if heterozygotic and homozygotic individuals

do not have the same phenotype

Page 8: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

• When the phenotype of the heterozygote is intermediate between the phenotypes of the two homozygotic genotypes, the disorder is considered to demonstrate incomplete dominance

• If the expression of both alleles can be detected in the presence of each other, the alleles are co-dominant.

Page 9: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Example• An child with a coding sequence change of

L444P in the both copies of the galactocerebrosidase gene has severe Gaucher disease.

• One parent of that child has one copy of the L444P change. This individual has no disease manifestations on the basis of physical, mental or radiographic examination

• Therefore the normal phenotype is dominant to the disease phenotype– We often say that the normal allele is dominant

Page 10: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Dominant and Recessive• The distinction is not absolute

– based on clinical phenotypes• therefore, it is arbitrary• not of significance at the level of gene action

– many recessive traits have manifestations at the cellular, biochemical or molecular levels

• sickle cell disease– mutation in the -globin gene so that glutamic acid is

changed to valine at amino acid 6– heterozygotes have a mild anemia and both products are

found by electrophoresis.» under appropriate conditions sickling can occur in the

RBCs of heterozygotes’» Therefore at the level of protein codominance, at the

level of physiologic function, incomplete dominance and clinically recessive

Page 11: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Dominant or Recessive

• Many recessive disorders are enzyme defects– enough activity exists in heterozygotes to allow

normal cellular/organ function

• In dominant disorders, disease occurs despite the presence of the normal allele– When one copy of a gene is not enough to prevent

disease, it is a condition of haploinsufficiency.– If the abnormal product interferes with the normal

product. a dominant negative effect exists.• example osteogenesis imperfecta

Page 12: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Other situations where one copy is not enough

• haploinsufficiency• dominant negative mutation• The mutant gene product may be enhanced

in one or more of its normal properties– achondroplasia

• Loss of a single copy is the first event in a several step cascade– predisposition to cancers– second mutation occurs at a somatic cellular level

Page 13: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Achondroplasia

Page 14: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Mimics of single gene disorder genetics

• Pedigree pattern simulates a single gene disorder

• teratogenic effects• inherited chromosomal disorders

– balanced translocations– contiguous gene syndromes– microdeletion disorders

• common environmental exposures

Page 15: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Factors affecting a pedigree pattern

• Age of onset– not all genetic disorders are congenital in their

expression• prenatal

– Thanatophoric dwarfism

• congenital– inborn errors of metabolism

• later in life– Huntington chorea

• Size of families– in small families the information to determine

inheritance pattern may not be present

Page 16: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Genetic Heterogeneity• A number of similar or identical phenotypes

are caused by different genotypes• albinism

– mutations at different loci• locus heterogeneity

– Text example Retinitis pigmentosa– look for different patterns of inheritance in different families

– may be the result of different mutations at the same locus

• allelic heterogeneity• some cases of allelic heterogeneity cause different

phenotypes– RET Dominant Hirschprung Dx, MEN types Iia or IIb

Page 17: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Autosomal Recessive Inheritance

• Disease occurs in individuals with two mutant alleles (either the same mutation of different ones)

• In general an individual inheritance a mutant allele from each parent– new mutations are generally rare

• Since each parent has two alleles – the chance of inheriting a mutant allele from one

parent is ½ and for the other parent is also ½– the net chance of inheritance two mutant alleles is

½ X ½ or 1/4

Page 18: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Punnett Square Way to illustrate various crosses in a simple diagram

Male

FemaleT t

t

TThomozygote (wild type)

Ttheterozygote

carrier

tthomozygote

mutant

T

Ttheterozygote

carrier

Page 19: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Punnett Squares 2

tt tt

tt ttt

t

t t

TT

TT

TT

TTT

T

T T

tt

tt

t

t

T

t Tt

Tt

Page 20: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Autosomal Recessive Inheritance

• Consanguinity– Parents have a common ancestor– The chances of inheriting an allele identical by descent

from both parents increases the chance of inheriting a recessive disorder

– Consanguinity is not the most common cause of individuals having autosomal recessive traits

• Genetic Isolation– Small populations of individuals with a common genetic

background may have increased risk of recessive disease– Ashkenazi :Tay-Sachs, Gaucher Disease– Finnish: Congenital Chloride-Losing Diarrhea

Page 21: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Characteristics of AR Inheritance

• Phenotype more likely in siblings of proband than in other relatives

• Males and females are equally affected

• Parents of an affected individuals are asymptomatic

• Recurrence risk for each sib is ¼

• Potential for consanguinity

Page 22: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Autosomal Dominant Inheritance

• Over half of the known Mendelian phenotypes are AD traits

• Incidence of some is very high– 1/500 Familial hypercholesterolemia– 1/2500-1/3000 Neurofibromatosis– 1/2500-1/3000 AD polycystic kidney disease

• New mutations are common– In a dominant lethal (pre-reproductive) disorder all

cases are due to new mutations

Page 23: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Autosomal Dominant Inheritance

• In a typical pedigree, every affected person has one affected parent

• Male to male transmission is possible• Equal numbers of affected females and males

are expected• One-half of the children of an affected

individual are expected to have inherited the dominant allele– Not all will express the mutant phenotype

• Phenotypically normal individuals generally do not transmit the mutant phenotype

Page 24: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Variation in the Phenotype

• Penetrance– the probability that a gene will have ANY phenotypic

expression• it is an all or none concept

• if some people with an appropriate genotype fail to express the phenotype, there is reduced penetrance

• Expressivity– Severity of the manifestations of the phenotype– when phenotypic severity varies among those with identical

genotypes, variable expressivity is shown

• Pleiotropy– Multiple phenotypic effects of a single gene or gene pair– when the effects are not obviously related

Page 25: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Neurofibromatosis, type 1• AD, 1/3000, 17q GTPase activating

protein/signal transduction• Almost complete penetrance by age 5 years • Clinical features

– Cafe-au-lait spots 94-100%

– Dermal neurofibromata– Axillary freckling– Lisch nodules (hamartomas) on iris 90-95% – Macrocephaly 45%– Short Stature 30-35%– Plexiform neurofibroma ~30%– Mental retardation ~5%– CNS tumors 3-10%– Scoliosis 10%

Page 26: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

NF1

• Less than half of infants show any sign of the disease– Lisch nodules develop over time (over 6 months of

age)– Cutaneous changes occur over time

• Mutation rate is very high– estimated to be 1/10,000

• Severity is unpredictable for new mutations or for inherited disease

Page 27: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Homozygotes for AD disorders

• Generally the result of matings of two heterozygous individuals– Achrondroplasia

• more severe phenotype• may not survive early infancy

– Familial hypercholesterolemia• Heterozygotes are 1/500 in population• Homozygotes 1/ million• While heterozygotes and homozygotes have elevated

cholesterol from birth, homozygotes have xanthomas early, die from MI by 30, hemodynamically like calcified Ao Stenosis

Page 28: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

X-linked Inheritance

• Phenotypes have a sex distribution which is characteristic

• Many of the genes have a disease phenotype• Males are hemizygous

– will express the disease phenotype if one mutation is present

– Females may be homozygous ore heterozygous• Heterozygotes may manifest the disease

Page 29: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Expression of X-linked Genes 1

• Lyon Hypothesis– In somatic cells of females only one X

chromosome is active– Inactivation occurs in early embryonic life– Ina any somatic cell either X chromosome may be

inactivated– Inactivation is random but permanent for the

descendent cells• inactivated X chromosomes can be recognized

cytologically in interphase cells as Barr bodies

Page 30: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

• An explanation for dosage compensation– Promoter region of many genes on the inactive X

are modified by methylation of cytosine in CpG dinucleotides altering packing of the chromatin

– Some genes are not inactivated (10-15%)• pseudoautosomal region (very distal short and long arms

of the X) for which matching sequence is present on the Y• genes for which related sequence is present on the Y• genes which are present only on the X and for which

expression levels are higher– steroid sulfatase (X-linked ichthyosis)

• Variable Expression of X-linked genes– manifesting heterozygotes– unbalanced inactivation

• mutation on the preferentially inactivated X – especially structurally abnormal X chromosomes

• Functional mosaicism

Page 31: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Are there X-linked Dominants?• Are there X-linked recessives

– expressed in all males but only in homozygous females

• Hemophilia A (Factor VIII deficiency)• X-linked color blindness

– as it is a relatively common disorder homozygotes are known

• X-linked Dominants– Expressed in heterozygotes

• if fully penetrant, all of the daughters and none of the sons of an affected male are themselves affected

• Vitamin D-resistant rickets

– X-linked lethal in hemizygotes• Retts syndrome• Incontientia pigmenti very non-random X-inactivation

Page 32: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Henry

Page 33: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

How Frequent are Genetic Diseases

• Estimated total incidence of genetic diseases vary– AD 3 – 9.5/1000 (1/200 people) with the most

common disorders being 1/1-2000– AR 2-2.5/1000– X-linked 0.5 – 2/1000– Chromosomal disorders 6-9/1000– Multifactorial disorders: 20 – 50/1000

• Most cancers, diabetes, heart disease, etc.

Page 34: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Inheritance modified by imprinting

• Prader-Willi and Angelman syndromes• In PWS about 70% have a cytologic deletion

15q11-15q13 on the paternally inherited chromosome

• In Angelman syndrome, the same cytological deletion is found in in 70% of the cases but it is always the maternally inherited chromosome

• The other 30% of the cases of PWS have uniparental disomy in which there are two copies of the maternally derived sequence

Page 35: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Uniparental Disomy

• Disomic cell line containing two chromosomes (or portions of chromosomes) inherited from only one parent.– isodisomy both sequences are identical– heterodisomy both homologs of a parent are

present– Implicated in Beckwith-Wiedermann syndrome

• loss of maternal genes or excess of paternal genes on 11p15

Page 36: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Mosaicism

• The presence of two or more genotypically distinct cell lines in an individual

• Somatic– Special case X-inactivation

• phenotypic mosaic

• Germline– gives rise to situations where the parent is

unaffected but the descendents have a mutation• phenotypic expression in ‘new mutations of AD’• seen in Factor VIII disease, Duchene muscular

dystrophy

Page 37: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Germline Mosaicism

• Suspected with the presence of two or more affected offspring with AD or X-linked disease in the absence of a family history

• Results from a parental clone with a somatic mutation in a germline cell/precursor

• Known to occur in some disorders frequently– Duchenne Muscular Dystrophy 14 - 15%– Hemophilia A 20%– Neurofibromatosis, type 1 – Achondroplasia?– Osteogenesis imperfecta, type 2 5 - 6%

Page 38: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

Maternal Inheritance of mtDNA

• Mitochondrial DNA (mtDNA) is inherited through the ovum not the sperm– Mother could pass it to all children

• Father will pass it to none of this children

• More than one copy of mtDNA are passed– mutations are common – more than one type of mtDNA genome is passed – effects of heteroplasy

• variable expression, pleiotropy, reduced penetrance

– functional somatic mosaic

Page 39: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

n

n

Symptomatic Asymptomatic

Loss of mutation

2n

Page 40: Single Gene Disorders Mendelian Inheritance History –Gregor Mendel (1822-1884) studied traits of garden pea plants All of the published information indicated

16 S12 S

ND 5

ND 4

ND 2

ND1

ND 6N

D3

ND

4L

CO II

CO I

CO III

CYTO B

L

V

F

MI

Q

K

D

S

Y

A NC

W

E

P

T

RG

SH

L

Human Mitochondrial

DNA Map

ATP 6

ATP 8

TAS

Ori7 S

D-loop

OH

OL