1. Chapter 13 Genes, Chromosomes, and Human Genetics

2. Fluorescent Probes Along a Human Chromosome
Fluorescent probes bound to specific sequences along human chromosome 10 (light micrograph). New ways of mapping chromosome structure yield insights into the inheritance of normal and abnormal traits.

3. Mickey and Fransie
Mickey Hayes and Fransie Geringer have progeria, a genetic disease that causes premature aging
The error is in the gene for lamin A, one of the lamin proteins that reinforces the inner surface of the nuclear envelope in animal cells
Children with progeria die from diseases of old age at an average age of 13
FIGURE 13.1 Two boys, both younger than 10, who have progeria, a genetic disorder characterized by accelerated aging and extremely reduced life expectancy.

4. 13.1 Genetic Linkage and Recombination
Chromosomes contain many genes, with each gene at a particular locus
Genes located on different chromosomes assort independently in gamete formation
Genes near each other on the same chromosome (linked genes) may be inherited together (linkage)

5. Principles of Linkage and Recombination
Thomas Hunt Morgan crossed a true-breeding fruit fly with normal red eyes and normal wings with a fly with recessive purple eyes and vestigial wings
In testcross offspring, he found a high number of parental phenotypes and a low number of recombinant phenotypes
Morgan proposed that pr and vg are physically associated on the same chromosome

6. Double mutant (purple eyes, vestigial wings)
Recombination
Testcross parents
pr+ vg+
pr vg
pr vg
Double mutant (purple eyes, vestigial wings)
F1 dihybrid (red eyes,
normal wings) X
FIGURE 13.3 Recombination between the purple-eye gene and the vestigial-wing gene, resulting from crossing-over between homologous chromosomes.
The testcross of Figure 13.2 is redrawn here showing the two linked genes on chromosomes. Chromosomes or chromosome segments with wild-type alleles are red, whereas chromosomes or segments with mutant alleles are blue. The parental phenotypes in the testcross progeny are generated by segregation of the parental chromosomes, whereas the recombinant phenotypes are generated by crossing-over between the two linked genes.

7. Recombination
Genetic recombination is a process in which two homologous chromosomes exchange segments with each other by crossing-over during meiosis
Recombination frequency – the percentage of testcross progeny that are recombinants can be used to determine the distance between two genes.

8. Chromosome Mapping
Linkage map of a chromosome show relative locations of genes
Based on recombination frequencies
The closer together two genes the greater chance they will be inherited together
Genes that are widely separated on a chromosome are so likely to undergo recombination that no linkage is detected between them – the genes assort independently
Crossing over disrupts linkages!

9. Relative Map Locations
long aristae
aristaless (short aristae)
long wings
dumpy wings
vestigial wings
gray red body eyes
black purple body eyes
red eyes
brown eyes
13.0
48.5
54.5
67.0
104.5
Drosophila chromosomes
III I IV II
Wild-type phenotypes
Mutant phenotypes
Y X
FIGURE 13.4 Relative map locations of several genes on chromosome 2 of Drosophila, as determined by recombination frequencies.
For each gene, the diagram shows the normal or “wild-type” phenotype on the top and the mutant phenotype on the bottom. Mutant alleles at two different locations alter wing structure, one producing the dumpy wing and the other the vestigial wing phenotypes; the normal allele at these locations results in normal long-wing structure. Mutant alleles at two different locations also alter eye color.

10. Genes Far Apart
Genes a and c are located so far apart that a crossover almost always occurs between them. Their linkage therefore cannot be detected.
Genes a and b, and b and c, however, are close enough to show linkage; a and c must there- fore also be linked.
57 mu
23 mu
34 mu a c b
FIGURE 13.5 Genes far apart on the same chromosome.
Genes a and c are far apart and will not show linkage, suggesting they are on different chromosomes. However, linkage between such genes can be established by noting their linkage to another gene or genes located between them—in this case, gene b.

11. 13.2 Sex-Linked Genes
Genes located on the sex chromosomes (sex-linked genes) are inherited differently in males and females
Genes located on chromosomes other than the sex chromosomes are called autosomes – they have the same patterns of inheritance in both sexes
In humans, chromosomes 1 to 22 are the autosomes

12. Sex Chromosomes in Humans
Females have two copies of the X chromosome, forming a homologous XX pair
produce only one type of gamete (X)
Males have one X chromosome and one Y chromosome, giving males an XY combination
produce two types of gametes (X and Y)
Sperm with an X chromosome fertilizes an X-bearing egg cell, results in an XX female
Sperm with a Y chromosome fertilizes an X-bearing egg cell, results in an XY male

13. Sex Chromosomes in Humans
Diploid cells in female parent
Diploid cells in male parent
Meiosis, gamete formation in both female and male:
Fertilization:
Sex chromosome combinations possible in new individual
Eggs X X
Sperm Y Y XX XY
X X
EyeWire/Getty Images
PhotoDisc, Inc/Getty Images
FIGURE Sex chromosomes and the chromosomal basis of sex determination in humans.
Females have two X chromosomes and produce gametes (eggs), all of which have the X sex chromosome. Males have one X and one Y chromosome and produce gametes, half with an X and half with a Y chromosome. Males transmit their Y chromosome to their sons, but not to their daughters. Males receive their X chromosome only from their mother.

14. Other Sex Chromosome Arrangements
Some insects have XX females and XO males
In birds, butterflies, and some reptiles, males have (ZZ) and females have ZW
In bees and wasps, sex is determined not by sex chromosomes but by whether the individual is haploid or diploid
Some eukaryotic microorganisms have a “sex” system specified by simple alleles of a gene

15. The Human Y Chromosome
Human sex determination depends on the SRY gene on the Y chromosome
The Y chromosome is small and only contains around 330 genes

16. Sex-Linked Genes
Alleles on sex chromosomes in males and females are inherited in a pattern called sex linkage
Alleles carried on the X chromosome occur in two copies in females, but in only one copy in males
Alleles carried on the Y chromosome are present in males, but not females

17. Sex-Linked Genes
X-linked genes on the X chromosome show patterns of X-linked inheritance
First discovered in Drosophila
Genes on the X chromosome can be passed from mothers to sons and daughters
Genes on the X chromosome can be passed from fathers only to daughters because fathers give a Y to their sons

18. Eye Color in Drosophila
A . Normal, red wild-type eye color
B. Mutant white eye color caused by recessive allele of a sex-linked gene on the X chromosome
Terry Gleason/Visuals Unlimited, Inc.
Science Source
FIGURE Eye color phenotypes in Drosophila.
Normal, red wild-type eye color.
Mutant white eye color caused by a recessive allele of a sex-linked gene carried on the X chromosome.

19. Evidence for Sex-Linked Genes
A. True-breeding red-eyed female X white-eyed male
P generation
Red eyes White eyes
White-eyed female X
red-eyed male
P generation
White eyes Red eyes X w+ w Y w+ w
F1 generation
Red eyes
All Fl flies have red eyes, white-eyes is recessive.
F1 generation
Red eyes
The Fl females have red eyes: Xw+Xw The Fl males all have white eyes: XwY because they received the Xw-bearing chromosome from the mother
Red eyes
White eyes
Females Xw+Xw, have red eyes. Males inherit Xw+Y, have red eyes. w+ w+ w+ w w w
F2 generation
F2 generation
Figure 13.8 Experimental Research: Evidence for Sex-Linked Genes.
Sperm
Sperm w+
All F2 females receive an Xw+. Half F2 males receive an Xw+ from mother. w
The F2 females show a phenotypic ratio of l red (Xw+Xw) : l white (XwXw), and the F2 males also show a phenotypic ratio of l red (Xw+Y) : l white (XwY). w+ w+ w + w + w + w +
Eggs w+
Eggs w w w+ w w w w w w
females males
All red-eyed females
1/2 red-eyed, 1/2 white-eyed males
1/2 red-eyed, 1/2 red-eyed,
1/2 white-eyed 1/2 white-eyed
3/4 red eyes : 1/4 white eyes
1/2 red eyes : 1/2 white eyes

20. X-Linked Genes in Humans
In humans, the inheritance of sex-linked genes can be determined by reconstructing the genotypes and phenotypes of past generations from family records (a pedigree)
X-linked recessive traits appear more frequently among males because males need to receive only one copy of the allele on the X chromosome to develop the trait
Females have a second allele that can mask the recessive traitmust receive two copies of the recessive allele, one from each parent, to develop the trait

21. Hemophilia: An X-Linked Trait
Queen Victoria was a heterozygous carrier for the recessive hemophilia allele (Xh+Xh) – she passed the mutant allele to her offspring, but did not have symptoms of the disease
In a pedigree, the trait alternates from generation to generation in males because a father does not pass his X chromosome to his sons
The X chromosome received by a male always comes from his mother

22. Hemophilia and Queen Victoria
Generation II I
III IV V VI
Edward
Duke of Kent (1767–1820)
Louis II Grand Duke of Hesse
George III
Victoria (1819–1901)
Albert
William Frederick
Irene Princess Henry
Alice of Hesse
Alexandra (Czarina Nicolas II)
Helena Princess Christian
Leopold Duke of Albany
Beatrice
Leopold Maurice
Alice of Athlone
Victoria Eugénie, wife of Alfonso XII ? 3 2
KEY
Carrier female Hemophilic male
? ? Status uncertain
Duke of Saxe- Coburg- Gotha
Earl Mount- batten of Burma
Waldemar Prince
Sigismund of Prussia
Henry
Viscount Trematon
3 Anastasia Alexis
females
Lady May Abel Smith
Rupert
Alfonso
Bettmann/Corbis
FIGURE 13.9 Inheritance of hemophilia in descendants of Queen Victoria of England.
The photograph shows the Russian royal family in which the son, Crown Prince Alexis, had hemophilia. His mother was a carrier of the mutated gene.

23. X Chromosome Inactivation
Females have twice as many X chromosomes as males
The effects are equalized in male and female mammals by a dosage compensation mechanism that inactivates one of the two X chromosomes in most body cells of females
A condensation process folds and packs the chromatin of one X chromosome into a tightly coiled state (Barr body) similar to the condensed state of chromosomes during cell division

24. X Chromosome Inactivation
Early during embryonic development one of the two X chromosomes in each cell is randomly inactivated – that same X is inactivated in all descendants of the cell
If the two X chromosomes carry different alleles of a gene, one allele will be active in some cell lines, and the other allele will be active in others
For some genes, X chromosome inactivation produces recognizably different effects in distinct regions of the body (e.g., calico cats)

25. Calico Color in Cats
Orange fur: O allele is active, masking phenotypic expression of the B gene
(an example of epistasis; see Section 12.2).
Active X Inactive X
Inactive X Active X
Autosome with
B fur color gene
White patches result from interactions with a different, autosomal gene that blocks pigment deposition in the fur completely. B
O (Allele for
orange fur color)
o (Mutant allele: no effect on fur)
Black fur: O allele is inactive because the X chromosome it is on is nactivated; the mutant o allele on the active X chromosome does not mask the phenotypic expression
of the B gene.
Cynthia Baldauf /Istockphoto.com
FIGURE A female cat with the calico color pattern in which patches of orange and black fur are produced by random inactivation of one of the two X chromosomes.
Two genes control the black and orange colors: The O allele on the X chromosome is for orange fur color, and the mutated o allele has no effect on color. The B gene on an autosome is for black fur color. A calico cat has the genotype Oo BB or Oo Bb; the former genotype is illustrated in the figure. An orange patch results when the X chromosome carrying the mutant o allele is inactivated. In this case, the O gene masks the expression of the B gene and orange fur is produced. (This example is of epistasis; see Section 12.2.) A black patch results when the X chromosome carrying the O allele is inactivated. In this case, the mutant o allele cannot mask B gene expression and black fur results. The white patches result from interactions with a different, autosomal gene that entirely blocks pigment deposition in the fur. In tortoiseshell cats, the same orange–black patching occurs as in calico cats but the gene for the white patching is not active.

26. 13.3 Chromosomal Mutations That Affect Inheritance
Chromosomal mutations are changes in chromosome structure or chromosome number
Changes in chromosome structure occur when the DNA breaks – the broken fragments may be lost, or attach to the same or different chromosomes
Changes in chromosome number include addition or loss of one or more chromosomes, or entire sets of chromosomes

27. Changes in Chromosome Structure
Deletion – A segment is lost from a chromosome
Duplication – A segment is broken from one chromosome and inserted into its homolog, adding to the ones already there
Translocation – A segment is attached to a different, nonhomologous chromosome
Inversion – A segment reattaches to the same chromosome, but in reversed orientation – the order of genes is reversed

28. Deletions and Duplications
A. Deletion
B. Duplication
Deletion of
segment F
FIGURE Chromosome deletion, duplication, translocation (a reciprocal translocation is shown), and inversion.

29. Altered chromosome 22 (Philadelphia chromosome)
Translocation
Normal chromosome 9
Altered chromosome 9
Normal chromosome 22
Altered chromosome 22 (Philadelphia chromosome)
BCR
ABL
Reciprocal translocation
gene
FIGURE Translocation found in many patients with a form of blood cancer called chronic myelogenous leukemia (CML).
A reciprocal translocation involving chromosomes 9 and 22 produce a short chromosome named the Philadelphia. On this chromosome the chromosome 9 ABL gene has become fused to the chromosome 22 BCR. The resulting overactivity of the ABL gene, which normally helps control cell division, causes the cell to convert to a cancer cell.

30. Translocation and Inversions
C. Reciprocal translocation
One chromosome
Reciprocal translocation
Non homologous chromosome
FIGURE Chromosome deletion, duplication, translocation (a reciprocal translocation is shown), and inversion.

31. Changes in Chromosome Number
Whole, single chromosomes may be lost or gained from cells through nondisjunction
the failure of homologous pairs to separate during the first meiotic division or of chromatids to separate during the second meiotic division
Individuals with extra or missing chromosomes are called aneuploids

32. Nondisjunction in Meiosis I
A. Nondisjunction during first meiotic division
Meiosis I Meiosis II
Gametes
Extra chromosome (n + l)
Extra chromosome (n + l)
Missing chromosome (n – l)
Nondisjunction
Nondisjunction during the first meiotic division causes both chromosomes of one pair to be delivered to the same pole of the spindle. The nondisjunction produces two gametes with an extra chromosome and two with a missing chromosome.
FIGURE Nondisjunction during (A) the first meiotic division and (B) the second meiotic division.

33. Nondisjunction in Meiosis II
Meiosis I Meiosis II
Gametes
Normal (n)
Normal
(n)
Missing chromosome (n – l)
Nondisjunction during the second meiotic division produces two normal gametes, one gamete with an extra chromosome and one gamete with a missing chromosome.
B. Nondisjunction during second meiotic division
Nondisjunction
Extra chromosme (n + l)
FIGURE Nondisjunction during (A) the first meiotic division and (B) the second meiotic division.

34. Aneuploids
In humans, addition or loss of an autosomal chromosome generally causes embryos to develop so abnormally that they naturally abort
Humans who receive an extra copy of chromosome 21 (trisomy 21) are born with Down syndrome – characterized by short stature and moderate to severe mental retardation

35. Incidence of Down syndrome
A. The chromosomes of a human female with Down syndrome showing three copies of chromosome 21 (circled in red) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
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
Incidence of Down syndrome
per 1,000 births 20 15
FIGURE Down Syndrome 10 5
Mothere’s age
c. Person with Down syndrome
R. Gino SantaMaria/Shutterstock.com

36. Aneuploidy of Sex Chromosomes
Unlike autosomal aneuploidy, altered numbers of X and Y chromosomes are often tolerated, producing individuals who grow to adulthood
XO (Turner syndrome) females have no Barr bodies, XXY (Klinefelter syndrome) males have one Barr body, and XXX (triple-X syndrome) females have two Barr bodies
People with a Y chromosome are externally male like, no matter how many X chromosomes are present

37. Abnormal Combinations of Sex Chromosomes
Resulting zygotes
Fertilization by normal sperm
XXY XO
XXX XX
Nondisjunction
(not viable) YO X
Turner syndrome O
Klinefelter syndrome
Triple-X syndrome Y
FIGURE Some abnormal combinations of sex chromosomes resulting from nondisjunction of X chromosomes in females.

38. Combinations of Sex Chromosomes in Humans

39. Changes in Sets of Chromosomes
Changes in chromosome number can also occur through duplication or loss of entire sets of chromosomes
Monoploids have one set of chromosomes
Individuals with more than the normal number of chromosomes are called polyploids
Triploids have three copies of each chromosome
Tetraploids have four copies of each chromosome
Hexaploids have six copies of each chromosome

40. 13.4 Human Genetic Traits, Pedigree Analysis, and Genetic Counseling
A number of human genetic conditions are caused by mutant alleles or chromosomal alterations that follow principles of Mendelian inheritance:
Autosomal recessive traits
Autosomal dominant traits
X-linked recessive traits
X-linked dominant traits

41. Autosomal Recessive Inheritance
Individuals who are homozygous for the dominant allele are free of symptoms and are not carriers
Heterozygotes are usually symptom-free, but are carriers
Homozygotes for the recessive allele show the trait
Unaffected parents have affected offspring
One affected parent has unaffected offspring

42. Autosomal Dominant Inheritance
People who are either homozygous or heterozygous for the dominant allele are affected
Individuals homozygous for the recessive normal allele are unaffected
Trait tends to be expressed in every generation
Affected individual has at least one affected parent
Usually passed to at least half the offspring

43. Pedigrees of Human Genetics TraitsII
III 3 4 1 2 5 6 7 8
A. Phenylketonuria (PKU): autosomal recessive
Generation I 9 10
B. Achondroplasia = autosomal domianamt
FIGURE Pedigrees of human genetics traits showing different modes of inheritance.
Part of a pedigree for phenylketonuria (PKU), an autosomal recessive trait.
Part of a pedigree for achondroplasia, an autosomal dominant trait.
Part of a pedigree for Duchenne muscular dystrophy (DMD), an X-linked recessive trait.
Part of a pedigree for hereditary enamel hypoplasia, an X-linked dominant trait.

44. X-Linked Recessive Traits
X-linked recessive inheritance
X-linked recessive traits appear more frequently among males because males need to receive only one copy of the allele on the X chromosome to develop the trait
Females must receive two copies of the recessive allele, one from each parent, to develop the trait
Mothers pass to sons and daughters
If a daughter has the trait, so does her father

45. X-Linked Dominant Traits
Only a few X-linked dominant traits have been identified in humans

46. Pedigrees of Human Genetics Traits7 8 3 4 6 5 9 1 2 II
C. Duchenne muscular dystrophy = x-linked recessive
Generation I
III
D. Hereditary enamel hypoplasia = x-linked dominant
FIGURE Pedigrees of human genetics traits showing different modes of inheritance.
Part of a pedigree for phenylketonuria (PKU), an autosomal recessive trait.
Part of a pedigree for achondroplasia, an autosomal dominant trait.
Part of a pedigree for Duchenne muscular dystrophy (DMD), an X-linked recessive trait.
Part of a pedigree for hereditary enamel hypoplasia, an X-linked dominant trait.

47. Predicting Human Genetic Disorders
Several approaches, including genetic counseling, prenatal diagnosis, and genetic screening, can reduce the number of children born with genetic diseases

48. Prenatal Diagnosis
In amniocentesis, cells are obtained from the amniotic fluid surrounding the embryo or fetus in the mother’s uterus
In chorionic villus sampling, cells are obtained from embryonic portions of the placenta
These tests can detect more than 100 genetic disorders

49. Amniocentesis
In amniocentesis, a syringe needle is inserted carefully through the uterine wall and a sample of amniotic fluid is taken. The procedure generally is performed before 12 weeks of development because of the risk to the fetus. Cells from the fetus in the extracted fluid are analyzed for genetic defects or chromosomal mutations.
Embryo and fetus
develops surrounded
by amniotic fluid to
Cushion it against shock.
FIGURE Amniocentesis, a procedure used for prenatal diagnosis of genetic defects.
The procedure is complicated and costly and, therefore, it is used primarily in high-risk cases.

50. Genetic Screening
Once a child is born, inherited disorders are identified by genetic screening, in which tests are routinely applied to children and adults or to newborn infants in hospitals

51. 13.5 Non-Mendelian Patterns of Inheritance
In cytoplasmic inheritance, the pattern of inheritance follows that of genes in the genomes of mitochondria or chloroplasts
In genomic imprinting, the expression of a nuclear gene is based on whether an individual organism inherits the gene from the male or female parent

52. Cytoplasmic Inheritance
Inheritance patterns of DNA found in chloroplasts and mitochondria (cytoplasmic inheritance) are different from those of genes in the nucleus
These genes usually show uniparental inheritance – all progeny (male and female) have the phenotype of only one of the parents
For most multicellular eukaryotes, offspring inherit only the mother’s phenotype (maternal inheritance)

53. Genomic Imprinting
Researchers have identified about 30 genes in mammals whose effects depend on whether an allele is inherited from the mother or the father (genomic imprinting)
The silent allele (the inherited allele that is not expressed) is called the imprinted allele
Example: Mouse insulin-like growth factor 2 (Igf2) gene
Only the paternally inherited gene has an effect on size
The maternal copy is imprinted