Inheritance

Dr. Zeyad Akawi Jreisat, M.D., M.A., Ph.D.

AUG

Intro n

Exon Transcription

TAA

mRNA
Translation

Protein

Chromosomal Theory of Inheritance

Chromosomes contain the genetic material that is transmitted from cell to cell and from parent to offspring Chromosomes are replicated and passed along generation after generation from parent to offspring. The nuclei of most eukaryotic cells contain chromosomes that are found in homologous pairs. During gamete formation, different types of chromosomes segregate independently of each other. Each parent contributes one set of chromosomes to its offspring.

Types of Inheritance
- Mendelian
- Autosomal dominant - Autosomal recessive - X-linked recessive - X-linked dominant - Nontraditional - Mitochondrial - Imprinting - Uniparental disomy - Mosaicism - Multi-factorial

Symbols for Pedigrees

Symbols for Pedigrees

 Pedigree: Expression of segregation or transmission of

traits within families.

Proband or index case: 1st family member seeking

medical attention (P).

Generation: Roman numbers (I, II, etc.). Individuals: Arabic numbers (1,2, etc.). Age: Next or below the symbol.

In order to understand Mendalian inheritance, several essential terms must first be defined

 Locus: A specific position on a chromosome. Alleles: alternative forms of a gene, or of a DNA

sequence, at a given locus.

Homozygous: both alleles at a locus are identical. Heterozygous: both alleles at a locus are different. A compound heterozygote: two different mutant
alleles at a given locus.

Double heterozygote: One mutant allele at each of two

different loci.

 Genotype: the genetic constitution or composition of an

individual.

Phenotype: the observed results of the interaction of the

genotype with environmental factors.

Genotype & Phenotype: are a musical analogy. Mendelian diseases: the result of a single mutant gene
that has a large effect on phenotype, inherited in a simple patterns.

Autosomal diseases: Encoded by genes on one of the

22 pairs of autosomes (non-sex chromosomes).

X-linked: encoded by a mutant gene on the X

chromosome.

A Comparison of Homologous Chromosomes

or

N Ab

Ab

Ab

Ab1

Ab2

Homozygous: Both alleles at a locus are the same.

Heterozygous: At the locus one gene is the wild type and the other mutant.

Compound heterozygote: Both allele are abnormal but different variations.

Mendelian genetics
Principle of segregation: Sexually reproducing organisms possess genes that occur in pairs and that only one member of this pair is transmitted to the offspring

Principle of independent assortment: genes at different loci are transmitted independently. In a reproductive event, a parent transmits one allele from each locus to its offspring and the allele transmitted at one locus has no effect on which allele is transmitted at the other locus

What is a trait?
Widows peak

ww

WW or Ww

How do we inherit a single trait?

We have to know the mode of inheritance
Dominant allele It is expressed when present It is designated with a capital (uppercase) letter An example is W for widows peak.

Recessive allele It is only expressed in the absence of a dominant allele. It is designated with a lowercase letter indicates An example is w for continuous hairline.

Proper use of the Punnett Square

A Punnett square can then be used to determine the phenotypic ratio among the offspring The punnett square can be used when it is hard to imagine the phenotypic ratio from any cross (i.e. Yy X Yy). Single gene: Yy X Yy = 3:1 Two genes: YyZz X YyZz = 9:3:3:1

Basic concepts of Probability

Laws of probability alone can be used to determine results of a cross. The laws are: Multiplication rule: the probability that two or more independent events will occur together is the product of their chances occurring separately. Addition rule: the chance that an event that can occur in two or more independent ways is the sum of the individual chances.

In the cross of Ww x Ww, what is the chance of obtaining either a W or a w from a parent?
Chance of W = , or chance of w = The probability of these genotypes is: The chance of WW = x = The chance of Ww = x = The chance of wW = x = The chance of ww = x = The chance of widows peak (WW, Ww, wW) is + + = or 75%.

Genotype versus Phenotype

Genotype refers to the genes of an individual which can be represented by two letters. Homozygous means that both alleles are the same; for example, WW stands for homozygous dominant ww stands for homozygous recessive.

Heterozygous means that the members of the allelic pair are different for example, Ww, a heterozygote

Genotype versus Phenotype

Phenotype refers to the physical or observable characteristics of the individual. Both WW and Ww result in widows peak, the phenotype is a widow's peak however, we have two genotypes resulting in the same phenotype. ww results in a straight hairline in this case, the phenotype can only result from one genotype

Genotype and gene frequency

The prevalence of many genetic diseases varies considerably from one population to another. The variation is due to the difference in proportion genotypes and alleles in a population.

Under simple conditions these frequencies can be estimated by direct counting. (MM: 64, MN: 120 and NN: 16) Total 200 subjects Genotype frequency = Genotype count/Total MM = 0.32; MN = 0.60; NN = 0.08 and the sum equal 1.

Gene (Allele) frequencies are easily estimated from genotype frequencies

How were allele frequencies estimated ? For Eskimo - Freq .of M = (0.835 + (0.5 x 0.156 )) = .913 Freq. of N = (0.009 + .(0.5 x 0.156 )) = .087

Example
Imagine that we have typed 200 individuals in a population for MN blood group, of these we have 64 with MM genotype, 120 with MN genotype and 16 with NN genotype. What is the genotype frequency? It is obtained simply by dividing each genotype count by the total number of subjects, for MM genotype it is 64/200 = 0.32 for MN genotype is 120/200 = 0.6 and for NN genotype is 16/200 = 0.08 the sum of these frequencies must equal 1

 What is the gene frequency? The gene frequency for each allele, M and N can be obtained by the process of gene counting. For M, each MM homozygous has two M alleles while each MN heterozygous has one allele therefore, the number of genes is (64 X 2) + 120 = 284 genes For N, each NN homozygous has two N alleles while each MN heterozygous has one allele therefore, the number of genes is (16 X 2) + 120 = 152 genes in total there are 400 genes at the MN locus To obtained the frequency of M, we divide the number of M allele by the total number of alleles at that locus 248/400 = 0.62 The same for the N allele, 152/400 = 0.38 The sum of the two frequencies must equal 1

Classification of genetic disorders

Single-gene disorders Chromosome disorders Multifactorial disorders

Single-gene disorders
Caused by mutations in individual genes. Mutations may be present in only one or both copies of a gene. Usually exhibit obvious and characteristic pedigree patterns.

Affect 2% of population sometime over an entire life span.

 Many important and well-understood genetic diseases are the result of a mutation in a single gene.
Single-gene or monogenic traits are also known as Mendelian traits. The variation in traits is caused by the presence of different alleles at individual loci Mendels key contributions to genetics were The principles of segregation Independent assortment The effects of one allele may mask those of another (dominance and recessiveness)

Autosomal Dominant and Recessive Inheritance

Autosomal dominant disorders

Expressed when only one chromosome of a pair carries the mutant allele. Normal allele on the homologous chromosome.

Simple dominant inheritance

Certain important features about autosomal dominant conditions

Careful questioning may reveal multigenerational family histories of problems vertical transmission pattern. Both sexes are involved equally.

50% risk to any child of an affected person.

Unaffected relatives do not transmit the phenotype to their children. Some individuals present with recognizable clinical pictures that reflect new mutations.

Certain important features about autosomal dominant conditions

Because dominant conditions are detectable in the presence of the normal allele of the responsible gene, their physiologic bases often, but not always, are related to aberrant structural or developmental problems. Dominant transmission includes the mechanism of socalled triplet repeat disorders. Dominant disorders often show pleiotropy. The severity or prominence of a particular aspect of a dominant disorder may be unpredictable variable expressivity. So-called dominant tumor syndromes provide clinical support for the Knudson hypothesis.

Variations in Autosomal Dominant Conditions

New mutations in the gamate formation. Decreased penetrance-obligate heterozygous for the mutation. Delayed onset of the disease. Germline mosaicism. The putative father is not the actual biological father.

Autosomal Dominant disorders examples

Achondroplasia Marfan syndrome Neurofibromatosis type 1 Dentinogenesis imperfecta Rieger syndrome (anodontia + iris dysplasia) Oculodentodigital syndrome Mandibulofacial dysostosis - Treacher Collins syndrome

Predicting inheritance pattern from pedigree

analysis
A man who had purple ears came to the attention of a human geneticist. The human geneticist did a pedigree analysis and made the following observations: In this family, purple ears proved to be an inherited trait due to a single genetic locus. The man's mother and one sister also had purple ears, but his father, his brother, and two other sisters had normal ears. The man and his normal-eared wife had seven children, including four boys and three girls. Two girls and two boys had purple ears. The purple-ear trait is most probably: A. autosomal, dominant B. autosomal, recessive C. sex-linked, dominant D. sex-linked, recessive E. cannot be determined from this information

 A. autosomal dominant, A genetic trait that is passed from generation to generation to generation, from both fathers to daughters and mothers to daughters, is typically autosomal dominant.

Recurrence risks for an autosomal dominant disorder

Parents at risk for producing children with a genetic disease are often concerned with the question: what is the chance that our future children will have this disease? When one or more children have already been born with a genetic disease, the parents are given a recurrence risk When the parents have not yet had children but are known to be at risk for having children with a genetic disease, an occurrence risk can be given Each birth is an independent event The occurrence and recurrence risks for each child are 1/2

Autosomal recessive disorders

Expressed only when both chromosomes of a pair carry a mutant allele.

Simple recessive inheritance

Several important aspects of recessive inheritance should be considered

Heterozygotes are generally unaffected clinically. An individual manifesting recessive disorder usually has heterozygous parents. Once a homozygote is identified, the recurrence risk for other mating of the same parents is 25%. Two-thirds of the unaffected siblings of an individual with an autosomal recessive disorder are likely to be heterozygotes. The likelihood that any two individuals selected randomly will be heterozygous for the same mutant allele is low.

Several important aspects of recessive inheritance should be considered

Consanguinity can lead to an increased likelihood of mating between heterozygotes. A homozygote must contribute one abnormal gene copy to any offspring because he or she has no normal copies of the gene at the responsible locus.

If a homozygote mates within a community where the frequency of heterozygotes is high (e.g., a geographically isolated community), a pattern resembling dominant inheritance may occur. Metabolic abnormalities are common in recessive disorders.
Quasidominant inheritance: recessive pattern that mimics that of an autosomal dominant trait

Autosomal recessive disorders examples

Cystic fibrosis Alpha 1-antitrypsin deficiency Congenital adrenal hyperplasia Phenylketonuria Tay-Sachs disease Sickle cell anaemia Albinism

Inheritance pattern for Tay Sachs Disease

A couple has a female child with Tay Sachs disease, and three unaffected children. Neither parent nor any of the four biological grandparents of the affected child has had this disease. The most likely genetic explanation is that Tay Sachs disease is inherited as a(n) ______________ disease. A. autosomal dominant B. autosomal recessive C. sex-linked recessive D. sex-linked dominant E. cannot make a reasonable guess from this information

 B. autosomal recessive; the disease is recessive because both parents are unaffected, and autosomal because a female child is affected but her father is not.

Recurrence risks for an autosomal recessive disorder

Many autosomal recessive diseases are severe enough that affected individuals are less likely to become parents The recurrence risk for the offspring of carrier parents is The recurrence risk for a carrier with a homozygous for the disease gene is (Quasidominant inheritance)

Dominant versus recessive: some cautions

A dominant disease allele will produce disease in a heterozygote, whereas a recessive disease allele will not A disease may be inherited in autosomal dominant fashion in some cases and in autosomal recessive fashion in others (familial isolated growth hormone deficiency, IGHD) Beta-thalassemia cases occurs as a result of autosomal recessive mutations, a small proportion inherited in autosomal dominant fashion

Factors that may complicate inheritance patterns

New mutations: It is estimated that 7/8 of all cases of achondroplasia are caused by new mutations, while only 1/8 are transmitted by achondroplastic parents. Germline mosaicism: Osteogenesis imperfecta type II, caused by mutations in the type I procollagen genes, achondroplasia, neurofibromatosis type I, Duchenne muscular dystrophy and hemophilia A.

Mosaicism
The presence of two or more cell lines with different genotypes within a single individual. May be chromosomal or single gene May or may not have an impact on the phenotype of the individual

Types Somatic Gonadal

Mosaicism
Somatic mutation Mutation which occurs after fertilization Neither parent has the altered genetic make-up Not every cell in the individual is defective Generally limited to dominant traits or chromosomal syndromes since only one defective unit is needed for expression If germ cells affected next generation at risk Clinical phenotype is depend on ratio of normal: abnormal.

Egg Normal

Sperm Normal

Zygote Normal

Mitosis

Mitosis

Abn

Abn

Abn

Mosaic Abnormal Cells Normal Cells

Mosaicism
Germinal (Germ-line) or gonadal mutations An individual who shows no clinical expression of a disease but a proportion of gametes contain a mutation for a genetic trait.

Risk to offspring may be as high as 50%

Has made geneticist cautious when counseling for recurrence risk for what seems to be a new mutation in a family.

What is the risk for indicated pregnancy?

P
Osteogenesis Imperfecta Autosomal dominant disease

Gonadal mosaicism
The affected child appears to be a de novo (new) mutation, because both parents are clinically normal and the condition is 100% penetrant. Without the risk of gonadal mosaicism, the risk for the new pregnancy would be the possibility of a new mutation about 1 in 10,000 to 100,000. But from data collected from multiple families the true risk is about 6% because of gonadal mosaicism.

Penetrance
Penetrance refers to the probability of any expression of a diseased phenotype during an individuals lifetime. Conditions where an abnormal genotype always show clinical symptoms are considered 100% penetrant. If a condition shows reduced penetrance, there is a chance the individual will have no clinical symptoms of the disease despite an abnormal genotype. (nonpenetrance) Offspring of the nonpenetrant individual would be at risk for clinical disease.

Penetrance Example
Hereditary breast cancer. Mutations in the BRCA1 gene are found in about 40 % of familial or hereditary breast cancer. At least 20% of women who inherit a gene associated with breast cancer will not develop cancer in their lifetime. These women would be considered nonpenetrant.

Factors that may complicate inheritance patterns

Reduced penetrance: an individual who has the genotype for a disease may not exhibit the disease phenotype at all, even though he or she can transmit the disease gene to the next generation (retinoblastoma). About 10% of the obligatory carriers of the retinoblastoma susceptibility gene do not have the disease. The penetrance of the gene is then said to be 90% Age dependent penetrance: a delay in the age of onset of a genetic disease. Examples, Huntington disease, familial Alzheimer disease, breast cancer.

Factors that may complicate inheritance patterns

Variable expression: the penetrance may be complete, but the severity of the disease can vary greatly, neurofibromatosis type I. Causes: - Environmental effects - Interaction of other genes (modifier genes) with the disease gene - Allelic heterogeneity (different types of mutations at the same disease locus), Example is beta-globin mutations that can cause either sickle cell disease or various beta-thalassemias Pleiotropy and heterogeneity: Pleiotropic, are genes that have more than one discernible effect on the body (Marfan syndrome). Locus heterogeneity, the causation of the same disease phenotype by mutations at distinct loci (Adult polycystic kidney disease, APKD can be caused by PKD1 mutation and by PKD2 mutation)

Neurofibromatosis type 1

Variable Expressivity in Holoprosencephaly

Marfan Syndrome

Genomic imprinting
The term imprinting implies a type of marking process that has a memory The term genomic imprinting refers to a situation where a segment of DNA is marked, and that mark is retained and recognized throughout the life of the organism inheriting the marked DNA Imprinted genes follow a Non-Mendelian pattern of inheritance The marking process causes the offspring to distinguish between maternally and paternally inherited alleles

Genomic imprinting
Depending on how the genes are marked, the offspring will express one of the two alleles, but not both Imprinting may involve a single gene, a part of a chromosome, an entire chromosome or even all the chromosomes from one parent Imprinting can be divided into three stages: - Establishment of the imprint during gametogenesis - Maintenance of the imprint during embryogenesis and in adult somatic cells - Erasure and reestablishment of the imprint in the germ cells

Genomic imprinting
Examples: Prader-Willi syndrome, gene defected encode for small nuclear riboprotein that is expressed in the brain (SNRPN) that inherited from the father Angelman syndrome, gene defected encodes for a protein involved in ubiquitin-mediated protein degradation during brain development that inherited from the mother - Seventy percent of the cases caused by chromosome deletion - These two diseases might be caused by uni-parental disomy (individual inherits two copies of a chromosome from one parent and none from the other), point mutation and by small deletion in imprinting center Beckwith-Wiedmann syndrome: minority of this disease is caused by the inheritance of two copies of a chromosome from the father and none from the mother (uni-parental disomy) Insulin-like growth factor 2 (IGF2): this gene is imprinted (inactive) on the maternally derived chromosome and active only on the paternal chromosome

The role of imprinting in the development of angelman and prader-willi syndromes

DNA methylation in the imprinting process