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
Arranged linearly in chromosomes

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

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

9. Gene Symbolism Normal alleles (wild-type) Wild-type Mutant
Usually most common allele
Designated by “+” symbol
Usually dominant
Wild-type Mutant
+ = red eyes pr = purple
+ = normal wings vg = 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

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

17. Recombination Frequency

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

19. Linkage Maps First genetic map
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
Proposed genes were located on the same 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%

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

26. Recombination Occurs Often
Widely separated linked genes often recombine
Seem to assort independently
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
XX: female
XY: male
Other chromosomes are called autosomes

30. Sex Determination in Humans

31. Human Sex Chromosomes Human X chromosome Human Y chromosome
Large (2,350 genes)
Many X-linked genes are nonsexual traits
Human Y chromosome
Small (few genes)
Very few match genes on X chromosome
Contains SRY gene
Regulates 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
Clues that there is a gene on the Y that determines maleness

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 Initiates a sex switch –
transcription factor
Initiates a sex switch –
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
If no SRY, the gonad develops into an ovary

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

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

42. Dosage Compensation
X-inactivation
Mary Lyon
Barr Body

43. Dosage Compensation X-inactivation XXY males have a Barr body
XO females have none
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 12th day of embryonic life

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

46. How is the X chromosome inactivated?

47. How is the X chromosome inactivated?
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
Coats the inactive X and is involved in gene silencing
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
Females have two X chromosomes
Heterozygote: recessive allele hidden (carrier)
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
Hemophilia: defective blood clotting protein

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

57. Color Blindness in Humans

60. Try this problem color-blind female color-blind male
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?
color-blind female
color-blind male
noncolor-blind female
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. c. Reciprocal translocation
One chromosome
Nonhomologous chromosome
Reciprocal translocation
Figure 13.11
Chromosome deletion, duplication, translocation (a reciprocal translocation is shown), and inversion.
Fig c, p. 266

65. Nondisjunction
Failure of homologous pair separation during Meiosis I

66. Nondisjunction
Failure of chromatid separation during Meiosis II

67. b. Nondisjunction Extra chromosome (n + 1) Missing chromosome (n – 1)
Normal
(n)
Figure 13.12
Nondisjunction during (a) the first meiotic division and (b) the second meiotic division.
Normal
(n)
Meiosis I
Meiosis II
Gametes
Nondisjunction during the second meiotic division produces two normal gametes, one gamete with an extra chromosome and one gamete with a missing chromosome.
Fig b, p. 267

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

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

70. Down Syndrome

71. a. 1 2 3 4 5 6 7 8 9 10 11 12
Figure 13.13: Down syndrome.
(a) The chromosomes of a human female with Down syndrome showing three copies of chromosome 21 (circled in red). 13 14 15 16 17 18 19 20 21 22 23
Fig a, p. 268

72. Incidence of Down syndromeb.
Incidence of Down syndrome
per 1000 births
Figure 13.13: Down syndrome.
(b) The increase in the incidence of Down syndrome with increasing age of the mother, from a study conducted in Victoria, Australia, between 1942 and 1957.
Mother’s age
Fig b, p. 268

73. Aneuploidy of Sex Chromosomes

74. Aneuploidy of Sex Chromosomes

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. Pictorial representation of a family history
Pedigree Analysis I
Pictorial representation of a family history

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

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

84. Autosomal Recessive Inheritance

85. Cystic Fibrosis

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

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

89. Autosomal Dominant Inheritance

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

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

94. X-Linked Recessive Inheritance

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

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

101. Genetic Counseling Identification of parental genotypes
Construction of family pedigrees
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
Amniotic fluid around embryo (amniocentesis)
Placenta (chorionic villus sampling)
Postnatal genetic screening
Biochemical and molecular tests

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

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

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

112. Matrilineal inheritance

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
Blood-stained hankie 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?

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?

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?

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

133. Cytoplasmic Inheritance
Mutant alleles in organelle DNA
Mendelian inheritance not followed (no segregation by meiosis)
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
Other allele is turned off (silenced)
Often, result of methylation of region adjacent to gene responsible for trait