Patterns of Inheritance (CYTOGENETICS) PDF

CYTOGENETICS 5 – INHERITANCE PATTERNS JAMAIKA IRA DG FABROA, RMT,DTA,ASCPI,MPH © I. NON-MENDELIAN INHERITANCE PATTERNS - Inheritance patterns that deviate from the fundamental laws of inheritance as stipulated by Gregor Mendel - Non-mendelian may be influenced by factors such a...

CYTOGENETICS 5 – INHERITANCE PATTERNS JAMAIKA IRA DG FABROA, RMT,DTA,ASCPI,MPH © I. NON-MENDELIAN INHERITANCE PATTERNS - Inheritance patterns that deviate from the fundamental laws of inheritance as stipulated by Gregor Mendel - Non-mendelian may be influenced by factors such as the location of the gene, whether it is inside or outside the nucleus, location of the gene on the chromosomes, effects of the environment, and variation in the properties of the protein encoded by different alleles of the gene. → NOT all genetic traits strictly follow the laws discovered by Gregor Mendel → Some variations can be observed in all animals including humans. → Four types of variations involving multiple genes/alleles: ∙ Incomplete dominance ∙ Codominance ∙ Polygenic inheritance ∙ Lethal Alleles ∙ Pleiotropy A. Incomplete/Partial Dominance → A condition where during the heterozygous condition (Bb) the dominant allele DOES NOT completely overpower the recessive allele, therefore, there is a “BLENDING” of the traits A. Incomplete/Partial Dominance Example #1: Incomplete Dominance in Four O’clock Plants A. Incomplete/Partial Dominance Example #2 B. Codominance →A condition when during the heterozygous condition (Bb) the dominant allele DOES NOT completely overpower the recessive allele, so, both traits are seen at the same time. B. Codominance → Example #1: Rabbits B. Codominance → Example #2: Rhododendrons B. Codominance → Example #3: Humans C. Polygenic Inheritance → Inheritance pattern for traits that are controlled by more than one gene. → Example is human height and skin complexion. Polygenic traits. The alleles of each gene have a minor additive effect on the phenotype. C. Polygenic Inheritance → Example #1: Skin Color C. Polygenic Inheritance → Example #2: Height C. Polygenic Inheritance → Example #2: Eye Color D. Lethal Genes → Genes capable of causing death of organism carrying them. → The gene responsible for pseudoachondroplasia (dwarfism) causes a dominant dwarfism but it is lethal when homozygous D. Lethal Genes → Example #1: Dwarfism D. Lethal Genes → Example #1: Dwarfism ▪ What is the probability of a dwarf child when a dwarf man marries a woman with normal stature? o Dwarf man genotype = Dd o Normal woman genotype = dd o Do a test cross D. Lethal Genes → Example #1: Dwarfism ▪ If two dwarves marry? o Dwarf father genotype = Dd o Dwarf mother genotype = Dd o Do a test cross  D. Lethal Genes → OTHER LETHAL GENES IN HUMANS: Example: → Non-deadly lethal gene: pattern baldness Male androgenetic alopecia (AGA) is the most common form of hair loss in men. It is characterized by a distinct pattern of progressive hair loss starting from the frontal area and the vertex of the scalp. E. Pleiotropy → When one gene affects multiple characteristics → Pleiotropy refers to the expression of multiple traits by a single gene. E. Pleiotropy → Example #1: Sickle-cell disease E. Pleiotropy Example #2: Marfan Syndrome OTHER NON-MENDELIAN INHERITANCE PATTERNS → Extranuclearinheritance o Maternal effect (also known as maternal influence) o Maternal inheritance (mitochondria/chloroplast) o Infectious heredity (cytoplasmic parasites) → Genomic imprinting → Mosaicism EXTRANUCLEAR INHERITANCE. → A specific phenotype is not controlled by genes on the chromosomes in the nucleus. o Maternal inheritance (also called cytoplasmic inheritance or mitochondrial inheritance) ▪ The transmission of traits through cytoplasmic genetic factors such as mitochondria or chloroplasts ▪ These cytoplasmic organelles are usually inherited with the egg’s cytoplasm form the mother.  EXTRANUCLEAR INHERITANCE. o Maternal effects ▪ An individual’s phenotype is controlled by gene products in the genome (e.g., proteins) of the mother (oocyte). → Non-nuclear DNA is often inherited uniparentally. → In humans, children get mitochondrial DNA from their mother (but not their father).  EXTRANUCLEAR INHERITANCE. MATERNAL INHERITANCE o Since mitochondria are inherited from the person’s mother, they find a way to trace maternal ancestry (line of descent through female ancestors o If there is a gene found in mitochondrial DNA that causes a disease or characteristic, that gene can be inherited from any of your maternal ancestry/line of descent.  EXTRANUCLEAR INHERITANCE. o Because of mutations in mitochondrial genes: ▪ There is HETEROPLASMY ∙ A cell with mutant and normal mitochondria ▪ There is HOMOPLASMY ∙ A cell has a uniform set of mitochondria: all completely normal mtDNA or completely mutant mtDNA  EXTRANUCLEAR INHERITANCE.  EXTRANUCLEAR INHERITANCE.. EXTRANUCLEAR INHERITANCE → What is the characteristic of the cells/tissue that are frequently affected by mutations in the mtDNA? o Those that have high energy demand ▪ CNS, the heart, and muscle (neuromuscular system): ▪ Encephalopathy, myopathy, ataxia, retinal degeneration, loss of function of the external ocular muscles ▪ LHON (Leber’s Hereditary Optic Neuropathy ▪ MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes). EXTRANUCLEAR INHERITANCE Mitochondria have their own genome of about 16,500 bp that exists outside of the cell nucleus. Each contains 13 protein- coding genes, 22 tRNAs, and 2 rRNAs. o They have a higher rate of substitution (mutations where one nucleotide is replaced with another) than nuclear DNA making it easier to resolve differences between closely related individuals. o They are present in large numbers in each cell, so fewer samples are required to construct an evolutionary tree. o They are inherited only from the mother, which allows tracing of a direct genetic line. o They don’t recombine. The process of recombination in nuclear DNA (except the Y chromosome) mixes sections of DNA from the mother and the father creating a garbled genetic history. EXTRANUCLEAR INHERITANCE → MATERNAL EFFECTS o An individual’s phenotype is controlled by gene products in the genome (e.g., proteins, mRNA) of the mother (oocyte). o The phenotype of the individual is not determined by its own genotype but by the genotype of the mother. o Example: Shell coiling in Lymnea peregra INFECTIOUS INHERITANCE o Refers to the inheritance of an agent that can be inherited with cytoplasm. o Such agent may be intracellular bacteria or viruses. o The presence of these agents can alter the function or survival of the cells they inhabit, and this in turn can change the phenotype of the organism. o Refers to the transmission of an infectious agent such as bacteria and viruses in the cytoplasm of a mother to offspring. GENOMIC IMPRINTING → Imprints are formed due to the differential methylation of paternal and maternal alleles. → This results in differing expression between alleles from the two parents. → Methylated DNA – low levels of gene expression → Unmethylated DNA – higher levels of gene expression MOSAICISM → Presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilized egg. → A result of mutations in the cells producing different populations of cells with different genes for a particular trait. MOSAICISM EXAMPLE 1: Heterochromia iridum MOSAICISM EXAMPLE 1: Cutaneous mosaicism PEDIGREE ANALYSIS ▪ Pedigree analysis determines if a trait is dominant, recessive, autosomal, or sex-linked. ▪ Usually, pedigrees are used to analyze the patterns of inheritance of a particular trait that runs in the family. ▪ This can show the presence or absence of a trait as it relates the relationship among the parents, offspring, and siblings. ▪ Geneticists can figure-out the genotype and phenotypes when analyzing the pedigree. PEDIGREE ANALYSIS/SYMBOLS PEDIGREE ANALYSIS/SYMBOLS SYMBOL FOR SEX ∙ Circle = Female ∙ Square = Male SYMBOL FOR TRAITS ∙ Clear Shapes = Unaffected Individual ∙ Shaded Symbol = Affected Individual ∙ Partial Shaded Symbol = Heterozygous Individual for a particular trait. Carrier of one dominant allele and the other is a recessive allele. PEDIGREE ANALYSIS/SYMBOLS PEDIGREE ANALYSIS/SYMBOLS PEDIGREE ANALYSIS/SYMBOLS PEDIGREE ANALYSIS/SYMBOLS PEDIGREE ANALYSIS/SYMBOLS PROPOSITUS / PRO-BAND Arrow on the LEFT SIDE of a symbol that points to the person of interest in a pedigree ▪ Symbols for miscarriage or abortion. Notes about the pregnancy before the event of miscarriage or abortion are placed. ▪ For pregnant women, estimated delivery date is also placed. ▪ Symbols are used and notes are placed in order to make the pedigree more informative. PATTERNS OF INHERITANCE → The interaction between alleles in heterozygotes may be: ∙ DOMINANT = One allele controls the phenotype. Ex. Yy - yellow Only one copy of allele is needed to show the disease/trait. o The dominant allele present will mask the effect of the recessive allele. RECESSIVE = The recessive allele does not control the phenotype. PEDIGREE: DOMINANT VS RECESSIVE ∙ DOMINANT One of the parents must have the trait. o One, if not both parents have the trait. Dominant traits will NOT skip a generation. o The trait is continuous in the affected family. ∙ RECESSIVE Neither parent is required to have the trait since they can be heterozygous. The trait may escape/skip a generation in the affected family. o It is possible that the parents may not have the trait, but the trait reemerged in the children. PEDIGREE: AUTOSOMAL VS SEX-LINKED ∙ AUTOSOMAL Both males and females are equally likely to be affected. (Usually in equal proportions) ∙ SEX-LINKED Usually X-linked o Ex. In X-linked recessive traits, males are much more commonly affected than females. PEDIGREE: AUTOSOMAL VS SEX-LINKED X- LINKED RECESSIVE TRAITS ∙ Son = Affected In most cases, Males are affected – the sons are affected. ∙ Daughter = Carrier If the female will inherit the gene, usually they serve as carrier – especially if one copy only. ▪ It is very rare to have homozygous recessive X chromosomes. ▪ It is always possible that the male offspring will show- up the disease. PEDIGREE: AUTOSOMAL VS SEX-LINKED EX. 1 ∙ A Sex-Linked Trait Mostly males are affected. ∙ A Sex-Linked Recessive Trait Parents are not affected, most likely that the parents are carriers. It skips generations. PEDIGREE: AUTOSOMAL VS SEX-LINKED EX. 2 ∙ An Autosomal Trait There is equal distribution of the trait to both sexes o It is not necessarily exactly 50:50 distribution but at least close to equal. ∙ An Autosomal Dominant Trait Within the affected families, the trait does not skip a generation. AUTOSOMAL DOMINANT → One mutated copy of the gene in each cell is sufficient for a person to be affected. → Each affected person usually has one affected parent. → The disorder tends to occur in every generation of an affected family. AUTOSOMAL RECESSIVE → Two mutated copies (Homozygous Recessive) of the gene are present in each cell. Usually, 25% of the offspring will show the disease. o 25% of the Offspring = Unaffected o 50% of the Offspring = Could be heterozygous. (Carriers) → Affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Recessive trait has a carrier state. AUTOSOMAL RECESSIVE TYPICAL PATTERN OF AUTOSOMAL RECESSIVE DISORDERS. ∙ An Autosomal Trait There is equal distribution of the trait to both sexes ∙ An Autosomal Recessive Trait It skips/escapes generations. → Autosomal recessive disorders are typically NOT seen in every generation of an affected family. X-LINKED DOMINANT INHERITANCE Example : Congenital Generalized Hypertrichosis X-LINKED DOMINANT INHERITANCE CRITERIA: 1. Expressed in females in one copy 2. Much More severe effects in males (because he has no other alleles to mask its effect). 3. High rates of miscarriage due to early lethality in males 4. Passed from male to all daughters but to no sons X-LINKED DOMINANT INHERITANCE X-LINKED DOMINANT INHERITANCE X-LINKED DOMINANT INHERITANCE X-LINKED RECESSIVE INHERITANCE CRITERIA: 1. Always expressed in the males. 2. Expressed in a female homozygote but rarely in a heterozygote 3. Passed from heterozygote or homozygote mother to affected son 4. Affected female has an affected father and mother who is affected or a heterozygote. X-LINKED RECESSIVE INHERITANCE X-LINKED RECESSIVE INHERITANCE X-LINKED RECESSIVE INHERITANCE ∙ Hemophilia A & B ∙ Bruton's agammaglobulinemia ∙ Wiskott-Aldrich syndrome ∙ G6PD deficiency ∙ Ocular albinism ∙ Lesch Nyhan syndrome ∙ Dystrophy (Duchenne's and Becker’s) ∙ Hunter's Syndrome X-LINKED RECESSIVE INHERITANCE → For both X-linked Dominant and Recessive: If mother is HOMOZYGOUS, ALL children will inherit one or two copies of the affected genes MATERNAL INHERITANCE Y-LINKED DOMINANT INHERITANCE Y-LINKED DOMINANT INHERITANCE PEDIGREE CHART INTERPRETATION Autosomal Dominant ∙ Appears in both sexes with equal frequency ∙ Both sexes transmit the trait to their offspring ∙ Does not skip generations ∙ Affected offspring must have an affected parent unless they possess a new mutation ∙ When one parent is affected (het.) and the other parent is unaffected, approx. ½ of the offspring will be affected ∙ Unaffected parents do not transmit the trait PEDIGREE CHART INTERPRETATION Autosomal Recessive ∙ Appears in both sexes with equal frequency ∙ Trait tend to skip generations ∙ Affected offspring are usually born to unaffected parents ∙ When both parents areheterozygous, approx. ¼ of the progeny will be affected ∙ Appears more frequently among the children of consanguine REMINDERS X-linked Dominant ∙ Both males and females are affected; often more females than males are affected ∙ Does not skip generations (since it is a dominant trait) ∙ Affected sons must have an affected mother ∙ Affected daughters must have either an affected mother or an affected father ∙ Affected fathers will pass the trait on to all their daughters ∙ Affected mothers if heterozygous will pass the trait on to the (50%) ½ of their sons and (50%) ½ of their daughters ∙ Every generation ∙ Father passes on to daughters only ∙ Mothers passes to sons (1/2) and daughters (1/2) REMINDERS X-linked Recessive ∙ More males than females are affected ∙ Affected sons are usually born to unaffected mothers, thus the trait skips generations ∙ Approximately ½ of carrier mothers’ sons are affected ∙ It is never passed from father to son ∙ All daughters of affected fathers are carriers ∙ Hemophilia – only males are affected and sons do not share the phenotypes of their fathers (X-linked), expression of hemophilia skips a generation  DEDUCING GENOTYPES 1. Know the mode of inheritance (Autosomal Dominant/Recessive or X-linked Dominant/Recessive or Mitochondrial inheritance, or Y-linked Dominant 1. Identify individuals who are homozygous recessive. It differs based on the mode of inheritance. 2. Do a test-cross to know the genotypes of the unknown individual. cross it against homozygous recessive that you have identified previously. REMEMBER! ∙ An individual if homozygous dominant if the offspring are all heterozygous. If the unknown parent is heterozygous cross it against homozygous recessive, it is possible that 50%of the offspring are heterozygous and 50% homozygous recessive EXAMPLE EXAMPLE QUESTIONS?