Chapter 5 Human Chromosomes and Chromosome Behavior

Human Chromosomes

• Humans contain 46 chromosomes, including 22 pairs of homologous autosomes and two sex chromosomes • Karyotype = stained and photographed preparation of metaphase chromosomes arranged according to their size and position of centromeres

Figure 05.01A: Human chromosome painting.

Figure 05.01B: Human chromosome painting.

Parts A and B Courtesy of Johannes Wienberg, Ludwig-Maximillians-University, and Thomas Ried, National Institutes of Health

Centromeres

• Chromosomes are classified according to the relative position of their centromeres • In metacentric it is located in middle of chromosome • In submetacentric — closer to one end of chromosome • In acrocentric — near one end of chromosome • Chromosomes with no centromere, or with two centromeres, are genetically unstable

Figure 05.F05: Three possible shapes of monocentric chromosomes in anaphase as determined by the position of the centromere (shown in dark blue).

Figure 05.F06: Human ancestors had 24 pairs of chromosomes. In the evolution of the human genome, two acrocentric chromosomes fused, creating human chrosome 2.

Human Chromosomes

• Each chromosome in karyotype is divided into two regions (arms) separated by the centromere • p = short arm (petit); q = long arm • p and q arms are divided into numbered bands and interband regions based on pattern of staining • Within each arm the regions are numbered.

Figure 05.03: Designations of the bands and interbands in the human karyotype.

Figure 05.F04: The human chromosome complement at metaphase of mitosis.

Sequence data from International Human Genome Sequencing Consortium, Nature 409 (2001): 860-921, and J.C. Venter, et al., Science 291 (2001): 1304-1351. Chromosome image courtesy of Michael R. Speicher. Institute of Human Genetics, Medical University of Graz.

Human X Chromosome

• Females have two copies of X chromosome.

• One copy of X is randomly inactivated in all somatic cells.

• • • Females are genetic mosaics for genes on the X chromosome; only one X allele is active in each cell.

Barr body = inactive X chromosome in the nucleus of interphase cells.

Dosage compensation equalizes the number of active copies of X-linked genes in females and males.

Figure 05.07: Schematic diagram of somatic cells of a normal female.

The calico cat shows visible evidence of X-chromosome inactivation.

Figure 05.08: Female cat heterozygous for the orange and black coat color alleles.

Human Y Chromosome

• • Y chromosome is largely heterochromatic.

Heterochromatin is condensed inactive chromatin.

• Important regions of Y chromosome: – pseudoautosomal region: region of shared X-Y homology – SRY – master sex controller gene testis determining factor (TDF) development that encodes for male

The pseudoautosomal region of the X and Y chromosomes has gotten progressively shorter in evolutionary time.

Figure 05.09: Progressive shortening of the mammalian X-Y pseudoautosomal region through time.

Data from B.T. Lahn and D.C. Page, Science 286 (1999): 964-967

Human Y Chromosome

• Y chromosome does not undergo recombination along most of its length, genetic markers in the Y are completely linked and remain together as the chromosome is transmitted from generation to generation • The set of alleles at two or more loci present in a particular chromosome is called a haplotype • The history of human populations can be traced through studies of the Y chromosome

Abnormal Chromosome Number

• Euploid = balanced chromosome abnormality = the same relative gene dosage as in diploids (example: tetraploids) • Aneuploid = unbalanced set of chromosomes = relative gene dosage is upset (example: trisomy of chromosome 21) • Monosomic = loss of a single chromosome copy Polysomic = extra copies of single chromosomes • Chromosome abnormalities are frequent in spontaneous abortions.

Abnormal Chromosome Number

• Monosomy or trisomy of most human autosomes is unviable. There are three exceptions: trisomies of 13, 18, and 21 • Down Syndrome is a genetic disorder due to trisomy 21, the most common autosomal aneuploidy in humans • Frequency of Down Syndrome increases with mother ’ s age • Monosomy usually results in more harmful effects than trisomy

Figure 05.F11: Risk of Down syndrome in the absence of prenatal screening as related to mother ’s age. Note that the scale on the vertical axis is logarithmic.

Data from J. K. Morris, D. E. Mutton, and E. Alberman, J. Med. Screen. 9 (2002): 2-6

Abnormal Chromosome Number

Table 05.01 Chromosome Abnormalities per 100,000 Recognized Human Pregnancies.

Abnormal Chromosome Number

• Trisomic chromosomes undergo abnormal segregation • Trivalent = abnormal pairing of trisomic chromosomes in cell division • Univalent = extra chromosome in trisomy is unpaired in cell division

Figure 05.12: Meiotic synapsis in a trisomic.

Sex Chromosome Aneuploidies

• An extra X or Y chromosome usually has a relatively mild effect due to single-active-X principle and relatively few genes in Y chromosome • Trisomy-X = 47, XXX (female) • Double-Y = 47, XYY (male) • Klinefelter Syndrome = 47, XXY (male, sterile) • Turner Syndrome = 45, X (female, sterile)

Abnormal Chromosome Number

• Aneuplody results from nondisjunction : a failure of chromosomes to separate and move to opposite poles of the division spindle • The rate of nondisjunction can be increased by chemicals in the environment.

Chromosome Deletions

• Deletions : missing chromosome segment • Polytene chromosomes of

Drosophila

can be used to map physically the locations of deletions • Any recessive allele that is uncovered by a deletion must be located inside the boundaries of the deletion: deletion mapping • Large deletions are often lethal

Figure 05.F13: Ectopic recombination between direct repeats in the same DNA molecules results in deletion of the material between the repeats.

Figure 05.F14: Mapping of a deletion by testcrosses. The F1 heterozygotes with the deletion express the recessive phenotype of all deleted genes.

Figure 05.F15: Polytene chromosomes from a larval salivary gland cell of Drosophila melanogaster.

© Andrew Syred/Photo Researchers, Inc.

Figure 05.16: Part of the X chromosome in polytene salivary gland nuclei and the extent of six deletions (I–VI) in a set of chromosomes.

Gene Duplications

• Duplication are genetics rearrangements in which chromosome segment present in multiple copies • Tandem duplications : repeated segments are adjacent • Tandem duplications often result from unequal crossing-over due to mispairing of homologous chromosomes during meiotic recombination Figure 05.17: Unequal crossing-over of tandem duplications.

Red-Green Color Vision Genes

• Genes for red and green pigments are close on X chromosome • Green-pigment genes may be present in multiple copies on the chromosome due to mispairing and unequal crossing-over • Unequal crossing-over between these genes during meiotic recombination can also result in gene deletion and color-blindness • Crossing-over between red- and green-pigment genes results in chimeric (composite) gene

Figure 05.19: Red-pigment and green-pigment genes.

Figure 05.F18: A standard color chart used in initial testing for color blindness. The pattern tests for an inability to distinguish red from green.

© Steve Allen/Brand X Pictures/Alamy Images

Figure 05.F19: (A) Organization of genes in three wildtype X chromosomes. (B) Origin of multiple green-pigment genes by unequal crossing-over.

Figure 05.F19: (A) Organization of genes in three wildtype X chromosomes. (B) Origin of multiple green-pigment genes by unequal crossing-over.

CNV with Reciprocal Risks of Autism and Schizophrenia

Figure 05.21: Origin of chromosomes bearing a duplication or deletion of a genomic region by means of unequal crossing-over between repeated sequences.

Figure 05.22: Comparison of some of the major symptoms of autism spectrum disorder and schizophrenia highlighting those that resemble polar opposits.

Chromosome Inversions

• Inversions are genetic rearrangements in which the order of genes in a chromosome segment is reversed • Inversions do not alter the genetic content • In an inversion heterozygote, chromosomes twist into a loop in the region in which the gene order is inverted Figure 05.24: Loop in the region in which the gene order is inverted.

Figure 05.F23: Ectopic recombination between inverted repeats results in an inversion.

Chromosome Inversions

• Paracentric inversion does not include centromere • Crossing-over within a paracentric inversion loop during recombination produces one acentric (no centromere) and one dicentric (two centromeres) chromosome

Figure 05.25: Crossover within the inversion loop.

Chromosome Inversions

• Pericentric inversion includes centromere • Crossing-over within a pericentric inversion loop during homologous recombination results in duplications and deletions of genetic information Figure 05.26: Synapsis between homologous chromosomes.

Reciprocal Translocations

• A chromosomal aberration resulting from the interchange of parts between nonhomologous chromosomes is called a translocation • There is no loss of genetic information, but the functions of specific genes may be altered • • Translocations may produce position effects : changes in gene function due to repositioning of gene Gene expression translocated gene may be elevated or decreased in

Reciprocal Translocation

• In heterozygous translocation , one pair of chromosomes interchanged their segments and one pair is normal • In homozygous translocation , both pairs interchanged their segments Figure 05.27: Two pairs of nonhomologous chromosomes in a diploid organism.

Reciprocal Translocations

• Synapsis involving heterozygous reciprocal translocation results in pairing of four pairs of sister chromatids – quadrivalent • Chromosome pairs may segregate in several ways during meiosis, with three genetic outcomes: adjacent-1 segregation, homologous centromeres separate at anaphase I, and gametes contain duplications and deletions

Reciprocal Translocation

• Adjacent-2 segregation : homologous centromeres stay together at anaphase I; gametes have a segment duplication and deletion • Alternate segregation : half the gametes receive both parts of the reciprocal translocation and the other half receive both normal chromosomes; all gametes are euploid, i.e. have normal genetic content, but half are translocation carriers

Reciprocal Translocation

• The duplication and deficiency of gametes produced by adjacent-1 and adjacent-2 segregation results in the semisterility of genotypes that are heterozygous for a reciprocal translocation • The frequencies of each outcome is influenced by the position of the translocation breakpoints, by the number and distribution of chiasmata, and by whether the quadrivalent tends to open out into a ring-shaped structure on the metaphase plate

Figure 05.28: A quadrivalent formed in the synapsis of a heterozygous reciprocal translocation.

Robertsonian Translocation

• A special case of nonreciprocal translocation is a Robertsonian translocation – fusion of two acrocentric chromosomes in the centromere region • Translocation results in apparent loss of one chromosome in karyotype analysis Figure 05.29: Formation of a Robertsonian translocation by fusion. • Genetic information is lost in the tips of the translocated acrocentric chromosomes

Robertsonian Translocation

• When chromosome 21 is one of the acrocentrics in a Robertsonian translocation, the rearrangement leads to a familial type of Down syndrome • The heterozygous carrier is phenotypically normal, but a high risk of Down syndrome results from aberrant segregation in meiosis • Approximately 3 percent of children with Down syndrome have one parent with such a translocation

Polyploidy

• Polyploid species have multiple complete sets of chromosomes • The basic chromosome set, from which all the other genomes are formed, is called the monoploid set • The haploid chromosome set is the set of chromosomes present in a gamete, irrespective of the chromosome number in the species.

Figure 05.31: Chromosome numbers in diploid and polyploid species of

Chrysanthemum.

Polyploidy

• Polyploids can arise from genome duplications occurring before or after fertilization • Two mechanisms of  asexual polyploidization: the increase in chromosome number takes place in meiosis through the formation of unreduced gametes that have double the normal complement of chromosomes  the doubling of the chromosome number takes place in mitosis. Chromosome doubling through an abortive mitotic division is called endoreduplication

Figure 05.F32: Formation of a tetraploid organism by (A) sexual polyploidization and (B) asexual polyploidization.

Polyploidy

• Autopolyploids have all chromosomes in the polyploid species derive from a single diploid ancestral • Allopolyploids have complete sets of chromosomes from two or more different ancestral species • Chromosome painting : chromosomes hybridized with fluorescent dye to show their origins • Plant cells with a single set of chromosomes can be cultured

Figure 05.33: Autopolyploids have chromosome sets from a single species; allopolyploids have chromosome sets from diffrerent species.

Polyploidy

• The grass family illustrates the importance of polyploidy and chromosome rearrangements in genome evolution • The cereal grasses (rice, wheat, maize, millet, sugar cane, sorghum, and other cereals) are our most important crop plants • Their genomes vary enormously in size: from 400 Mb found in rice to 16,000 Mb found in wheat

Polyploidy

• In spite of the large variation in chromosome number and genome size, there are a number of genetic and physical linkages between single-copy genes that are remarkably conserved in all grasses amid a background of rapidly evolving repetitive DNA • Each of the conserved regions (synteny groups) be identified in all the grasses and referred to a similar region in the rice genome. can

Figure 05.37: Conserved linkages (synteny groups) between rice genome and other grass species. Data from G. Moore, Curr. Opin. Genet. Dev. 5 (1995): 717-724.

Figure 05.F36: Production of a diploid from a monoploid by treatment with colchicine.