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Genes, Chromosomes, and Human Genetics. Genetic Linkage and Recombination  The principles of linkage and recombination were determined with Drosophila.

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Presentation on theme: "Genes, Chromosomes, and Human Genetics. Genetic Linkage and Recombination  The principles of linkage and recombination were determined with Drosophila."— Presentation transcript:

1 Genes, Chromosomes, and Human Genetics

2 Genetic Linkage and Recombination  The principles of linkage and recombination were determined with Drosophila  Recombination frequency can be used to map chromosomes  Widely separated linked genes assort independently

3 Chromosomes  Genes Sequences of nucleotides in DNA Sequences of nucleotides in DNA Arranged linearly in chromosomes Arranged linearly in chromosomes

4 Linked Genes  Genes carried on the same chromosome Linked during transmission from parent to offspring Linked during transmission from parent to offspring Inherited like single genes Inherited like single genes Recombination can break linkage Recombination can break linkage

5 Drosophila melanogaster  Fruit fly Model organism for animal genetics Model organism for animal genetics Compared to Mendel’s peas Compared to Mendel’s peas Used to test linkage and recombination Used to test linkage and recombination

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9 Gene Symbolism  Normal alleles (wild-type) Usually most common allele Usually most common allele Designated by “+” symbol Designated by “+” symbol Usually dominant Usually dominant Wild-type Mutant Wild-type Mutant + = red eyespr = purple + = normal wingsvg = vestigial wings

10 Genetic Recombination  Alleles linked on same chromosome exchange segments between homologous chromosomes  Exchanges occur while homologous chromosomes pair during prophase I of meiosis

11 Evidence for Gene Linkage

12 Linked genes  Genes that are close together on the same chromosome  Belong to the same linkage group

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14 Linkage and Recombination  Linkage; genes are inherited together  Crossing over produces recombination – breaks up the association of genes that are linked

15 Notation for linkage  AABB X aabb

16 Recombination Frequency  Amount of recombination between two genes reflects the distance between them  The greater the distance, the greater the recombination frequency Greater chance of crossover between genes Greater chance of crossover between genes

17 Recombination Frequency

18 Mapping of Genes  Where is the gene is located on a chromosome? Linkage maps – Linkage maps – A chromosome map; abstract based on recombinant frequenciesA chromosome map; abstract based on recombinant frequencies Physical maps – Physical maps – Mapping the positions of cloned genomic fragmentsMapping the positions of cloned genomic fragments

19 Linkage Maps  First genetic map Alfred Sturtevant in the lab of Thomas Hunt Morgan Alfred Sturtevant in the lab of Thomas Hunt Morgan Observed that some pairs of genes do not segregate randomly according to Mendel’s principle of independent segregation Observed that some pairs of genes do not segregate randomly according to Mendel’s principle of independent segregation Proposed genes were located on the same chromosome Proposed genes were located on the same chromosome Variation in the strength of linkage determined how genes were positioned on the chromosome Variation in the strength of linkage determined how genes were positioned on the chromosome

20 Chromosome Maps  Recombination frequencies used to determine relative locations on a chromosome Linkage map for genes a, b, and c:

21 Map: Drosophila Chromosome

22 Predicting the outcomes of crosses with linked genes Determining proportions of the types of offspring requires knowing the RF

23 RF = 16%

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25 Gene mapping with RFs  Genetic maps Calculated by RFs Calculated by RFs Measured in map units or centimorgans (cM) Measured in map units or centimorgans (cM) RF can not exceed 50%, at 50% cannot distinguish between genes on the same or different chromosomes RF can not exceed 50%, at 50% cannot distinguish between genes on the same or different chromosomes Double crossovers – underestimate distance Double crossovers – underestimate distance

26 Recombination Occurs Often  Widely separated linked genes often recombine Seem to assort independently Seem to assort independently Detected by testing linkage to genes between them Detected by testing linkage to genes between them

27 Sex-Linked Genes  In both humans and fruit flies, females are XX, males are XY  Human sex determination depends on the Y chromosome

28 Sex-Linked Genes  Sex-linked genes were first discovered in Drosophila  Sex-linked genes in humans are inherited as they are in Drosophila  Inactivation of one X chromosome evens out gene effects in mammalian females

29 Sex Chromosomes  Sex chromosomes determine gender X and Y chromosomes in many species X and Y chromosomes in many species XX: female XX: female XY: male XY: male  Other chromosomes are called autosomes

30 Sex Determination in Humans

31 Human Sex Chromosomes  Human X chromosome Large (2,350 genes) Large (2,350 genes) Many X-linked genes are nonsexual traits Many X-linked genes are nonsexual traits  Human Y chromosome Small (few genes) Small (few genes) Very few match genes on X chromosome Very few match genes on X chromosome Contains SRY gene Contains SRY gene Regulates expression of genes that trigger male developmentRegulates expression of genes that trigger male development

32 Conclusions  At least one copy of X is required for human development  Male-determining gene is on the Y; a single copy produces a male regardless of the number of X’s  Absence of Y is female  Genes affecting fertility are on the X and Y  >X’s produces physical and mental disabilities

33 Sex determination in humans  Sex reversed individuals XX males and XY females XX males and XY females  Clues that there is a gene on the Y that determines maleness

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35 Proof that SRY is the male-determining gene Experiment in mice

36 SRY gene  When mouse sry was injected into the genome of a XX zygote, the transgenic female mice developed as males (sterile)

37 Function of SRY  DNA binding protein transcription factor transcription factor  Initiates a sex switch – Acts on genes in the undifferentiated gonad, transforming it into a testis Acts on genes in the undifferentiated gonad, transforming it into a testis Once the testis has developed testosterone is produced for male secondary sex characteristics Once the testis has developed testosterone is produced for male secondary sex characteristics If no SRY, the gonad develops into an ovary If no SRY, the gonad develops into an ovary

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39 Androgen Insensitivity  If the androgen receptor (AR) is deleted or null in function then testosterone can not act and no maleness results  Results from a mutation in the AR

40 Evolution of the Y  BioInteractive's Animation Console: Y Chromosome BioInteractive's Animation Console: Y Chromosome BioInteractive's Animation Console: Y Chromosome

41 Hey ! Females have two X’s and males only have one! Females are superior?

42 Dosage Compensation  X-inactivation Mary Lyon Mary Lyon Barr Body

43 Dosage Compensation  X-inactivation XXY males have a Barr body XXY males have a Barr body XO females have none XO females have none Barr body is the inactivated X Barr body is the inactivated X

44 Dosage Compensation  X-inactivation In human females an X chromosome is inactivated in each cell on about the 12 th day of embryonic life In human females an X chromosome is inactivated in each cell on about the 12 th day of embryonic life

45 Dosage Compensation  X-inactivation X-inactivation is random in a given cell X-inactivation is random in a given cell Heterozygous females show mosaicism at the cellular level for X-linked traits Heterozygous females show mosaicism at the cellular level for X-linked traits

46 How is the X chromosome inactivated?

47 X inactivation specific transcript (Xist) gene

48 X-inactivation center (XIC)  Gene for XIST Encodes an XIST RNA which is expressed solely from the inactive X-chromosome Encodes an XIST RNA which is expressed solely from the inactive X-chromosome Coats the inactive X and is involved in gene silencing Coats the inactive X and is involved in gene silencing Several genes remain active (PAR and others) Several genes remain active (PAR and others)

49 Calico Cats  Heterozygote female (no male calico cats)

50 Barr Body  Tightly coiled condensed X chromosome  Attached to side of nucleus  Copied during mitosis but always remains inactive

51 Sex Linkage  Female (XX): 2 copies of X-linked alleles  Male (XY): 1 copy of X-linked alleles  Only males have Y-linked alleles

52 Sex Linkage  Males have only one X chromosome One copy of a recessive allele results in expression of the trait One copy of a recessive allele results in expression of the trait  Females have two X chromosomes Heterozygote: recessive allele hidden (carrier) Heterozygote: recessive allele hidden (carrier) Homozygote recessive: trait expressed Homozygote recessive: trait expressed

53 Eye Color Phenotypes in Drosophila  Normal wild-type: red eye color  Mutant: white eye color

54 Evidence for Sex-Linked Genes

55 Human Sex-Linked Genes  Pedigree chart show genotypes and phenotypes in a family’s past generations  X-linked recessive traits more common in males Red-green color blindness Red-green color blindness Hemophilia: defective blood clotting protein Hemophilia: defective blood clotting protein

56 Inheritance of Hemophilia  In descendents of Queen Victoria of England

57 Color Blindness in Humans

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60 Try this problem  Red-green color blindness is X-linked recessive. A woman with normal color vision has a father who is color-blind. The woman has a child with a man with normal color vision. Which phenotype is NOT expected? a. color-blind female b. color-blind male c. noncolor-blind female d. noncolor-blind male

61 Chromosomal Alterations That Affect Inheritance  Most common chromosomal alterations: deletions, duplications, translocations, and inversions  Number of entire chromosomes may also change

62 Chromosomal Alterations  Deletion: broken segment lost from chromosome  Duplication: broken segment inserted into homologous chromosome

63 Chromosomal Alterations  Translocation: broken segment attached to nonhomologous chromosome  Inversion: broken segment reattached in reversed orientation

64 Fig c, p. 266 c. Reciprocal translocation Reciprocal translocation One chromosome Nonhomologous chromosome

65 Nondisjunction  Failure of homologous pair separation during Meiosis I

66 Nondisjunction  Failure of chromatid separation during Meiosis II

67 Fig b, p. 267 Meiosis IMeiosis IIGametes Missing chromosome (n – 1) Extra chromosome (n + 1) b. Nondisjunction during the second meiotic division produces two normal gametes, one gamete with an extra chromosome and one gamete with a missing chromosome. Normal (n) Normal (n) Nondisjunction

68 Changes in Chromosome Number  Euploids Normal number of chromosomes Normal number of chromosomes  Aneuploids Extra or missing chromosomes Extra or missing chromosomes  Polyploids Extra sets of chromosomes (triploids, tetraploids) Extra sets of chromosomes (triploids, tetraploids) Spindle fails during mitosis Spindle fails during mitosis

69 Aneuploids  Abnormalities usually prevent embryo development  Exception in humans is Down syndrome Three copies of chromosome 21 (trisomy 21) Three copies of chromosome 21 (trisomy 21) Physical and learning difficulties Physical and learning difficulties Frequency of nondisjunction increases as women age Frequency of nondisjunction increases as women age

70 Down Syndrome

71 Fig a, p a

72 Fig b, p. 268 b. Incidence of Down syndrome per 1000 births Mother’s age

73 Aneuploidy of Sex Chromosomes

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75 Human Genetics and Genetic Counseling  In autosomal recessive inheritance, heterozygotes are carriers and homozygous recessives are affected by the trait  In autosomal dominant inheritance, only homozygous recessives are unaffected

76 Human Genetics and Genetic Counseling  Males are more likely to be affected by X- linked recessive traits  Human genetic disorders can be predicted, and many can be treated

77 Modes of Inheritance  Autosomal recessive inheritance  Autosomal dominant inheritance  X-linked recessive inheritance

78 Pedigree Analysis I Pictorial representation of a family history

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82 Autosomal Recessive Inheritance  Males or females carry a recessive allele on an autosome  Heterozygote Carrier Carrier No symptoms No symptoms  Homozygote recessive Shows symptoms of trait Shows symptoms of trait

83 Autosomal recessive traits  Appear In equal frequency in both sexes In equal frequency in both sexes Only when a person inherits two alleles for the trait (one from each parent) Only when a person inherits two alleles for the trait (one from each parent) To skip generations (Heterozygotes unaffected) To skip generations (Heterozygotes unaffected)  Ex. Tay Sachs  Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease

84 Autosomal Recessive Inheritance

85 Cystic Fibrosis

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87 Autosomal Dominant Inheritance  Dominant gene is carried on an autosome  Dominant gene is carried on an autosome  Homozygote dominant or heterozygote Show symptoms of the trait Show symptoms of the trait  Homozygote recessive Normal Normal

88 Autosomal dominant traits  Appear In equal frequency in both sexes In equal frequency in both sexes Both sexes can transmit the trait Both sexes can transmit the trait Does not skip generations unless acquired as a new mutation Does not skip generations unless acquired as a new mutation  Ex. Familial hypercholesterolemia  OMIM - HYPERCHOLESTEROLEMIA, AUTOSOMAL DOMINANT OMIM - HYPERCHOLESTEROLEMIA, AUTOSOMAL DOMINANT OMIM - HYPERCHOLESTEROLEMIA, AUTOSOMAL DOMINANT

89 Autosomal Dominant Inheritance

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92 X-Linked Recessive Inheritance  Recessive allele carried on X chromosome  Males Recessive allele on X chromosome Recessive allele on X chromosome Show symptoms Show symptoms  Females Heterozygous carriers, no symptoms Heterozygous carriers, no symptoms Homozygous, show symptoms Homozygous, show symptoms

93 X-linked recessive traits  Appear more frequently in males more frequently in males Passed from unaffected female to males Passed from unaffected female to males Skips generations Skips generations  Ex. Hemophilia A  Hemophilia A Hemophilia A Hemophilia A

94 X-Linked Recessive Inheritance

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97 X-linked dominant traits  Appear more frequently in females more frequently in females Affected men pass the trait to all of their daughters and none of their sons Affected men pass the trait to all of their daughters and none of their sons Do not skip generations Do not skip generations  Ex. Hypophosphatemia  OMIM - HYPOPHOSPHATEMIA, X- LINKED OMIM - HYPOPHOSPHATEMIA, X- LINKED OMIM - HYPOPHOSPHATEMIA, X- LINKED

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99 Y-linked traits  Appear Only males are affected Only males are affected Affected men pass the trait to all of their sons Affected men pass the trait to all of their sons Do not skip generations Do not skip generations  Ex. Hairy ears  OMIM - HAIRY EARS, Y-LINKED OMIM - HAIRY EARS, Y-LINKED OMIM - HAIRY EARS, Y-LINKED

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101 Genetic Counseling  Identification of parental genotypes Construction of family pedigrees Construction of family pedigrees Prenatal diagnosis Prenatal diagnosis  Allows prospective parents to reach an informed decision about having a child or continuing a pregnancy

102 Genetic Counseling Techniques  Prenatal diagnosis tests cells for mutant alleles or chromosomal alterations  Cells obtained from: Embryo Embryo Amniotic fluid around embryo (amniocentesis) Amniotic fluid around embryo (amniocentesis) Placenta (chorionic villus sampling) Placenta (chorionic villus sampling)  Postnatal genetic screening Biochemical and molecular tests Biochemical and molecular tests

103 Prenatal genetic testing  Ultrasonography  Aminocentesis  CVS – chorionic villus sampling  Karyotype  Maternal blood tests  PGD

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107 Postnatal genetic testing  Newborn screening, ex. PKU  Heterozygote screening, ex. Tay Sachs  Presymptomatic testing, ex. Huntington

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109 Interaction between Sex and Heredity

110 Cytoplasmic inheritance  Characteristics encoded by genes in the cytoplasm  Cytoplasmic organelles inherited from the egg  Extensive phenotypic variation – no mechanism to ensure proper segregation  Ex. Mitochondrial genes

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112 Matrilineal inheritance

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115 Russian Revolution  July 16, 1918 a firing squad executed the tsar, his family, and attendants  Skeletal remains found in 1979

116 Are the skeletal remains actually Nicholas II and his family?  Evidence: Younger brother’s Grand Duke Georgij femur and tibia Younger brother’s Grand Duke Georgij femur and tibia Blood-stained hankie from Nicholas II Blood-stained hankie from Nicholas II Hair clippings from Nicholas II Hair clippings from Nicholas II

117 Discrepancy in the number of skeletons  Tsar, his wife, 5 children, 3 servants and physician  9 skeletons were found – how to explain the discrepancy?

118 Nuclear DNA  Nuclear DNA from the skeletons established that the skeletons were a family group  The DNA matched a father and three daughters

119 How to prove the skeletons were those of the royal family?

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121 Prince Philip’s DNA  Scientists used Prince Philip’s mitochondrial DNA to prove that the skeletons were the remains of Alexandra and her three daughters  Why mitochondrial DNA?

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125 To establish identity of Nicholas II  To establish the identity of Nicholas II scientists needed living relatives – why?

126 Relatives  Xenia – direct female descendent of the tsar’s sister  James – descends from a line that is connected to Nicholas II through his grandmother

127 Not a perfect match  Xenia = James but does not match Nicholas II  T at position 16,169  Nicholas there is a mixture of C and T  How can this be?

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130 Nicholas II other brother Georgij  Exhumation of Nicholas II other brother Georgij had an examination of his mitochondrial DNA also contained the heteroplasmy confirming the remains were that of Nicholas II

131 Nontraditional Patterns of Inheritance  Cytoplasmic inheritance follows the pattern of inheritance of mitochondria or chloroplasts  In genomic imprinting, the allele inherited from one of the parents is expressed while the other allele is silent

132 Cytoplasmic Inheritance  Genes carried on DNA in mitochondria or chloroplasts  Cytoplasmic inheritance follows the maternal line Zygote’s cytoplasm originates from egg cell Zygote’s cytoplasm originates from egg cell

133 Cytoplasmic Inheritance  Mutant alleles in organelle DNA Mendelian inheritance not followed (no segregation by meiosis) Mendelian inheritance not followed (no segregation by meiosis) Uniparental inheritance from female Uniparental inheritance from female

134 Human Mutations in Mitochondrial Genes

135 Genomic Imprinting  Expression of an allele is determined by the parent that contributed it Only one allele (from either father or mother) is expressed Only one allele (from either father or mother) is expressed  Other allele is turned off (silenced) Often, result of methylation of region adjacent to gene responsible for trait Often, result of methylation of region adjacent to gene responsible for trait


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