1 Introduction to Human Genetics Dr PupakDerakhshandeh, PhD Dr Pupak Derakhshandeh, PhD Ass Prof of Medical Science of Tehran University

2 General Background single gene disorders: –diseases or traits : phenotypes are largely determined : of mutations at individual loci

3 chromosomal abnormalities: –diseases where the phenotypes : physical changes in chromosomal structure - deletion, inversion, translocation, insertion, rings, etc –chromosome number - trisomy or monosomy, or in chromosome origin - uniparental disomy

4 multifactorial traits: –diseases or variations: phenotypes are strongly influenced : mutant alleles at several loci

5 mitochondrial inheritance: –Diseases: phenotypes are affected by mutations of mitochondrial DNA

6 diseases of unknown etiology: –"run in families"

7 Mendelian traits, or single gene disorders autosomal recessive inheritance : –the locus: on an autosomal chromosome –both alleles : mutant alleles to express the phenotype

8 By effect on function Loss-of-function mutations Gain-of-function mutations Dominant negative mutations Lethal mutations

9 Loss-of-function mutations Wild type alleles typically encode a product necessary for a specific biological function If a mutation occurs in that allele, the function for which it encodes is also lost The degree to which the function is lost can vary

10 Loss-of-function mutations gene product having less or no function: –Phenotypes associated with such mutations are most often recessive: –to produce the wild type phenotype! Exceptions are when the organism is haploid or when the reduced dosage of a normal gene product is not enough for a normal phenotype (haploinsufficiency)

11 Mendelian traits, or single gene disorders autosomal dominant inheritance : –the locus : on an autosomal chromosome –only one mutant allele : for expression of the phenotype

12 Loss-of-function mutations mutant allele will act as a dominant: the wild type allele may not compensate for the loss-of-function allele the phenotype of the heterozygote will be equal to that of the loss-of-function mutant (as homozygot) –to produce the mutant phenotype !

13 Loss-of-function mutations Null allele: –When the allele has a complete loss of function it is often called an amorphic mutation Leaky mutations: –If some function may remain, but not at the level of the wild type allele The degree to which the function is lost can vary

14 Gain-of-function mutations change the gene product such that it gains a new and abnormal function These mutations usually have dominant phenotypes Often called a neomorphic mutation A mutation in which dominance is caused by changing the specificity or expression pattern of a gene or gene product, rather than simply by reducing or eliminating the normal activity of that gene or gene product

15 Gain-of-function mutations Although it would be expected that most mutations would lead to a loss of function it is possible that a new and important function could result from the mutation: –the mutation creates a new allele: associated with a new function Genetically this will define the mutation as a dominant

16 Mendelian traits, or single gene disorders X-linked recessive inheritance: –the locus :on the X chromosome –both alleles : mutant alleles to express the phenotype in females

17 Mendelian traits, or single gene disorders X-linked dominant inheritance: –the locus: on the X chromosome –only one mutant allele : for expression of the phenotype in females

18 Non Mendelian traits gene disorders mitochondrial inheritance: –the locus : the mitochondrial "chromosome"

19 Mitosis cell division responsible for the development of the individual from the zygote somatic cells divide and maintain the same chromosomal complement each chromosome duplicates forming two chromatids connected to a single centromere

20 centromeres the centromeres line up on the metaphase plate the centromeres line up on the metaphase plate without the homologous pairing without the homologous pairing recombination found in meiosis exception for sister chromatid exchange of identical DNA information in mitosis exception for sister chromatid exchange of identical DNA information in mitosis centromere divides each chromatid : becomes a daughter chromosome at anaphase of cell division centromere divides each chromatid : becomes a daughter chromosome at anaphase of cell division two identical daughter cells with identical DNA complements two identical daughter cells with identical DNA complements

21 Mitosis Mutations: during DNA replication in mitosis these mutations: in somatic cell diseases, such as cancer most mitotic divisions/the fastest rate of growth: –before birth in the relatively protected environment of the uterus –Most of us only increase 15 to 30 times our birth weight

22 Meiosis (I)

23 Meiosis (II)

24 PEDIGREE CONSTRUCTION

25 AUTOSOMAL RECESSIVE INHERITANCE

26 AUTOSOMAL RECESSIVE INHERITANCE affected individuals: normal phenotypes one in ten thousand live births heterozygote frequency in the population: one in fifty

27 The Punnett Square for autosomal recessive diseases with an affected child in the family Within the normal siblings of affected individual : the probability of being a carrier is 2/3

28 hallmarks of autosomal recessive inheritance Males and females: equally likely to be affected the recurrence risk to the unborn sibling of an affected individual : 1/4 Parents of affected children: may be related The rarer the trait in the general population, the more likely a consanguineous mating is involved

29 Autosomal recessive inheritance

30 rare autosomal recessive diseases individuals in the direct line of descent within the family : carriers those individuals from outside the family are considered homozygous normal those individuals from outside the family are considered homozygous normal

31 AUTOSOMAL DOMINANT INHERITANCE

32 Autosomal dominant diseases usually rare To produce a affected homozygote: two affected heterozygotes would have to mate they would have only a 1/4 chance of having a normal offspring In the extremely rare instances: – where two affected individuals have mated: the homozygous affected individuals : usually are so severely affected they are not compatible with life

33 Autosomal dominant diseases The mating of very closely related individuals: –two affected individuals to know each other, isn’t forbidden in our society in most matings: affected individuals : heterozygotes –the other partner will be homozygous normal

34 Autosomal dominant diseases new mutations: –rare in nature every affected individual: an affected biological parent Males and females : –an equally likely chance of inheriting the mutant allele The recurrence risk of each child of an affected parent : –1/2 Normal siblings of affected individuals: – do not transmit the trait to their offspring

35 The defective product of the gene usually a structural protein, not an enzyme Structural proteins : usually defective: –one of the allelic products is nonfunctional enzymes usually : –require both allelic products to be nonfunctional to produce a mutant phenotype

36 The Punnett Square for autosomal recessive One gamete comes from each parent Two out of the four possible combinations: affected two out of four: normal two out of four: normal

37 AUTOSOMAL DOMINANT INHERITANCE

38 AUTOSOMAL DOMINANT INHERITANCE Variable Expressivity Late Onset High Recurrent Mutation Rate Incomplete Penetrance

39 VARIABLE EXPRESSIVITY (AD) One example : Marfan syndrome autosomal dominant disease caused by:a mutation in collagen formation It affects about 1/60,000 live births Symptoms of Marfan syndrome –skeletal –Optical –cardiovascular abnormalities Skeletal abnormalities: –arachnodactyly (long fingers and toes) –extreme lengthening of the long bones

40 dislocation of the lens of the eye

41 VARIABLE EXPRESSIVITY (AD) Marfan syndrome Optical abnormalities: –a dislocation of the lens of the eye Cardiovascular abnormalities –responsible for the shorter life span of Marfan syndrome patients Each patient may express all of the symptoms, or only a few! Each patient may express all of the symptoms, or only a few! That is variable expressivity Each patient with the mutant allele for Marfan syndrome: – expresses at least one of the symptoms

42 VARIABLE EXPRESSIVITY (AD) Marfan syndrome Almost all are taller than average Almost all have long fingers Some may be very mildly affected and lead normal lives while others, more severely affected: have a shorter life expectancy The disease : –recurrent mutations

43 LATE ONSET (AD) Some autosomal dominant diseases : do not express themselves until later in life the disease: passed the mutant allele along to their offspring before they themselves know they are affected In some cases even grandchildren are born before the affected grandparent shows the first signs of the disease

44 LATE ONSET (AD) Huntington disease (Huntington's Chorea): choreic movements expressed Progressive a good example of a late onset disease a good example of a late onset disease Age of onset varies from the teens to the late sixties with a mean age of onset between ages 35 and 45

45 Huntington disease Nearly 100% of the individuals born with the defective allele will develop the disease by the time they are 70 The disease : progressive with death usually occurring between four and twenty-five years after the first symptoms develop The disease : progressive with death usually occurring between four and twenty-five years after the first symptoms develop

46 Huntington disease (AD) At the gene level: the expansion of an unstable trinucleotide repeat sequence the expansion of an unstable trinucleotide repeat sequenceCAG “POLYGLUTAMINE DISEASES” Somatic mutations: expansion of trinucleotide repeat sequences in the coding region of the gene to produce a mutant allele

47 (AD): Other diseases (AD): myotonic dystrophy: an autosomal dominant disease expression is delayed expansion of unstable trinucleotide sequences CTG

48 myotonic dystrophy unstable sequence lies in a non- translated region of the gene the size of the inherited expansion correlates to the age of onset or the severity of disease

49 Repeats in non-coding sequences

50 HIGH RECURRENT MUTATION RATE Achondroplasia: the major causes of dwarfism Motor skills may not develop as quickly as their normal siblings but intelligence is not reduced about 1/10,000 live births

51 Achondroplasia Almost 85% of the cases : new mutations both parents have a normal phenotype The mutation rate for achondroplasia may be as much as 10 times the "normal" mutation rate in humans This high recurrent mutation is largely responsible for keeping the mutant gene in the population at its present rate

52 INCOMPLETE PENETRANCE It should never be confused with variable expressivity variable expressivity: –the patient always expresses some of the symptoms of the disease –and varies from very mildly affected to very severely affected incomplete penetrance: –the person either expresses the disease phenotype or he/she doesn't

53 Incomplete penetrance and variable expressivity are phenomena associated only with dominant inheritance, never with recessive inheritance

54 INCOMPLETE PENETRANCE in a known autosomal dominant disease

55 X-LINKED DOMINANT INHERITANCE

56 X-LINKED DOMINANT INHERITANCE A single dose of the mutant allele will affect the phenotype of the female! A recessive X-linked gene: –requires two doses of the mutant allele to affect the female phenotype –The trait is never passed from father to son

57 X-LINKED DOMINANT INHERITANCE All daughters of an affected male and a normal female are affected (100%) All sons of an affected male and a normal female are normal (100%) Mating of affected females and normal males produce 1/2 the sons affected and 1/2 the daughters affected (50% :50%) Males are usually more severely affected than females The trait may be lethal in males

58 X-LINKED DOMINANT INHERITANCE Males: usually more severely affected than females in each affected female: there is one normal allele producing a normal gene product and one mutant allele producing the non- functioning product while in each affected male there is only the mutant allele with its non-functioning product and the Y chromosome, no normal gene product at all

59 X-LINKED DOMINANT INHERITANCE All daughters are affected (100%) / All sons are normal (100%)

60 One example of an X-linked dominant: incontinentia pigmenti (IP) extremely rare The main features occur in the skin where a blistering rash occurs in the newborn period brown swirls a "marble cake-like" appearance on the skin the eyes central nervous system Teeth nails, and hair The severity varies from person to person

61 incontinentia pigmenti

62 key for determining: X-L D/AD to look at the offspring of the mating of an affected male and a normal female If the affected male has an affected son: –then the disease is not X-linked

63 What happens when males are so severely affected that they can't reproduce? This is not uncommon in X-linked dominant diseases There are no affected males: – to test for X-linked dominant inheritance to see if the produce all affected daughters and no affected sons !!!

64 What happens when males are so severely affected that they can't reproduce? Next pedigree shows the effects of such a disease in a family There are no affected males only affected females, in the population!

65 X-linked dominant inheritance (severe)

66 X-LINKED RECESSIVE INHERITANCE

67 X-LINKED RECESSIVE INHERITANCE They are, in general, rare Hemophilia (A/B) Duchenne muscular dystrophy Becker muscular dystrophy Lesch-Nyhan syndrome

68 X-LINKED RECESSIVE INHERITANCE More common traits: glucose-6-phosphate dehydrogenase deficience color blindness

69 A rare X-linked recessive disease

70 The hallmarks of X-linked recessive inheritance the disease is never passed from father to son Males are much more likely to be affected than females If affected males cannot reproduce, only males will be affected All affected males in a family are related through their mothers Trait or disease is typically passed from an affected: –grandfather, through his carrier daughters, to half of his grandsons

71 X-linked recessive inheritance

72 SEX LIMITED INHERITANCE

73 SEX LIMITED INHERITANCE In some X-linked recessive: diseases, such as Duchenne muscular dystrophy In some X-linked recessive: diseases, such as Duchenne muscular dystrophy –expression of the disease phenotype is limited exclusively to males In some X-linked dominant traits, such as incontinentia pigmenti : – expression is limited to females –males do not survive to term There are autosomal diseases that are limited to expression in only one sex: –Precocious puberty / beard growth are factors expressed only in males – The hereditary form of prolapsed uterus is expressed only in females DMD incontinentia pigmenti

74 MITOCHONDRIAL INHERITANCE

75 MITOCHONDRIAL INHERITANCE A few human diseases: to be associated with mitochondrial inheritance Leber optic atrophy : a disease of mitochondrial DNA The ovum, originating in the female 100,000 copies of mitochondrial DNA the sperm, originating in the male has fewer than 100 copies, and these are probably lost at fertilization Virtually all of ones mitochondria come from his, or her, mother Affected fathers produce no affected offspring while the offspring of affected mothers are affected The DNA of mitochondria contains about ten

76 Mitochondrial inheritance pattern

77 IMPRINTING

78IMPRINTING 1/10,000 and 1/30,000 live births for some genes: the origin of the gene may be important For some loci: – the gene inherited from the father –acts differently from the gene inherited from the mother –even though they may have the same DNA

79 Prader-Willi syndrome About 75% of patients with Prader-Willi syndrome : – a small deletion of the long arm of chromosome 15 this deletion is on the paternal chromosome (the father's genes are missing)

80 Prader-Willi syndrome

81 Angelman syndrome When this deletion is on the maternal chromosome (the mother's genes are missing) Angelman syndrome results

82 Angelman syndrome

83 uniparental disomy The two diseases have very different clinical symptoms a rare chromosomal event in which both chromosomes come from a single parent (mother or father) both chromosomes 15 are derived from the mother: Prader-Willi syndrome When both chromosomes 15 are derived from the father: Angelman syndrome

84 normal development an individual inherit one copy of this chromosomal region from his or her father and one from his or her mother Several other regions : show uniparental disomy without this effect on the phenotype! Several other regions : show uniparental disomy without this effect on the phenotype! Small deletions usually affect the phenotype but they produce the same phenotype whether of maternal or paternal origin Imprinting represents an exception to Mendel's laws and remains an important area of research Imprinting represents an exception to Mendel's laws and remains an important area of research

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