Brs genetics pdf

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We hope that the new edition of BRS Biochemistry, Molecular Biology, and Genetics becomes a valuable tool for students seeking high-yield resources as they. BRS Genetics addresses a field that is increasingly taught in shorter courses. Chapters are written in an outline format and include pedagogical features such as. Lippincott Williams Wilkins, - pp. t highlights most tested topics from USMLE Step 1. Nearly board-style questions. BRS Genetics.


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BRS soundofheaven.info Stephanie Ha. soundofheaven.info 06/02/ PM Page i Aptara Genetics soundofheaven.info 06/02/ PM Page ii. Highlight, take notes, and search in the book. BRS Cell Biology and Histology (Board Review Series) BRS Biochemistry, Molecular Biology, and Genetics (Board Review. I haven't taken my Board exam yet, but I believe this is a good review and pre-test study guide for anyone who is a student of genetics. There is a good review.

This results in a 46,XX karyotype with all nuclear chromosomes of pater- nal origin. Therefore, the heterozygous female will be mildly to overtly affected i. DNA packaging. Cyber Monday Sale. Can heterozygous females ever show signs of an X-linked recessive disorder? The double 35S::

Minisatellite DNA is composed of moderately-sized blocks 0. The function of microsatellite DNA is not known. Transposons are mobile DNA sequences that jump from one place in the genome to another called transposition. Types of transposons. Short interspersed nuclear elements SINEs. When Alu repeats are located within genes, they are confined to introns and other untranslated regions. Long interspersed nuclear elements LINEs.

Long terminal repeat LTR transposons. DNA transposons. Most DNA transposons in humans are no longer active i. Mechanism of transposition Figure A,B. Conservative transposition. In conservative transposition, the transposon jumps as dou- ble-stranded DNA. Transposase a recombination enzyme similar to an integrase cuts the transposable element at a site marked by inverted repeat DNA sequences about 20 base pairs long. Transposase is encoded in the DNA of the transposable element.

The transpo- son is inserted at a new location, perhaps on another chromosome. A,B Mechanisms of transposition. A Conservative Transposition. B Retrotransposition. C-F Transposons and genetic variability. F Gene Transfer. In retrotransposition, the transposon jumps through a RNA inter- mediate.

The transposon undergoes transcription, which produces a RNA copy that encodes a reverse transcriptase enzyme. The transposon is inserted at a new location using the enzyme integrase. This mechanism is similar to the mecha- nism that a RNA virus retrovirus uses in its life cycle to transform host DNA.

Transposons and genetic variability Figure C-F. The main effect of transposons is to affect the genetic variability of the organism. Transposons can do this in several ways: Mutation at the former site of the transposon. After the transposon is cut out of its site in the host chromosome by transposase, the host DNA must undergo DNA repair.

A mutation may arise at the repair site. Level of gene expression. If the transposon moves to the target DNA near an active gene, the transposon may affect the level of expression of that gene.

While most of these changes in the level of gene expression would be detrimental to the organism, some of the changes over time might be beneficial and then spread through the population. Gene inactivation. If the transposon moves to the target DNA in the middle of a gene sequence, the gene will be mutated and may be inactivated. Gene transfer. If two transposons happen to be close to one another, the transposition mechanism may cut the ends of two different transposons. This will move the DNA between the two transposons to a new location.

If that DNA contains a gene or an exon sequence , then the gene will be transferred to a new location. This mechanism is espe- cially important in development of antibiotic resistance in bacteria.

If the bacterial DNA between to the two transposons contains the gene for tetracycline resist- ance, then other bacteria will become tetracycline resistant. The remaining with an imprint of the opposite sex. DNA sequence. A noncoding DNA 5. Which of the following is the D pseudogenes most likely explanation for how this occurs? The central dogma of molecular biology is inactivated in a majority of cells in the is that DNA is transcribed into RNA, which is body. The translation B Triplet repeat expansion.

Which of the C Incomplete penetrance. A year-old woman is diagnosed as hav- trol ing a complete molar pregnancy with C protein-coding genes, RNA-coding enlargement of the chorionic villi and genes, and epigenetic control absence of an embryo.

Cytogenetic analysis D protein-coding genes, processed pseudo- of the products of conception revealed a genes and retrogenes, and epigenetic 46,XX karyotype.

The molar pregnancy was control caused by which one of the following? The genomes of a number of organisms, A preeclampsia including humans, have now been charac- B two haploid sets of paternal chromosomes terized and compared.

Which of the follow- C trophoblastic neoplasia ing describes one of the findings of these D elevated hCG levels endeavors? E enlarged uterus A There is a correspondence between the 4. Which of the following is a characteristic biological complexity of an organism and of genomic imprinting? B There is a correspondence between the A Most genes must bear the parent of ori- biological complexity of an organism and gin imprint for proper expression. B The parent of origin copy to be imprinted C There is a correspondence between the differs from gene to gene, and most biological complexity of an organism and genes require an imprint.

C The phenotype of a child with Prader D There is no correspondence between the Willi syndrome is different depending on biological complexity of an organism and whether the child has a deletion on chro- the amount of coding DNA, noncoding mosome 15 or UPD for the chromosome. DNA, or the number of chromosomes. Genetic variability in an organism Which noncoding DNA is found near the including humans is significantly affected telomeres of the chromosomes?

Which one of the following is the mecha- 9. The most abundant sequence in the nism responsible for genomic imprinting?

The answer is A. Noncoding DNA such as introns, pseudogenes, and repetitive elements such as satellite DNA make up the rest of the genome. The answer is E. The other RNAs participate in the processes of transcription and translation but are not components of the ribosomes. The answer is B. Because of genomic imprinting, both maternal and paternal haploid sets of chromosomes are required for normal development.

When there are two paternal hap- loid sets of chromosomes in a conceptus, a placenta will develop but not an embryo. Imprinting does not change the DNA sequence of a gene. The maternal and paternal copies of genes are mostly active or silent at the same time.

The end result of a deletion of chromosome 15 or UPD is that there are no paternal copies of the gene s involved in the syndrome, so there is no difference in phenotype. If the normal gene is inactivated in a large enough number of cells, then there would be more defective gene products present than normal gene products and dis- ease symptoms will be the result. The answer is C. Although protein-coding genes account for much of what are recognized as heritable traits, RNA-coding genes and epigenetic control are also important in gene expression, both normal and abnormal.

What has been determined so far is that the amount of noncoding DNA corresponds with the biological complexity of an organism. The number of chromosomes has no correspondence with biologi- cal complexity. For example, carp a fish have chromosomes and humans have Transposons can cause mutations in their former site when they relo- cate, alter gene expression at sites where they integrate, inactivate a gene by integrating somewhere in its sequence, and move pieces of nontransposon DNA to a new location in the genome.

Although much of the time this is a detrimental event, sometimes the changes are beneficial and spread through the population. The answer is D. Alu repeats are located in the GC rich, R-band positive areas of the chro- mosome that contain many genes.

There are many copies of the other sequences in the human genome, but they are not as abundant as the Alu sequences. Methylation plays a crucial role in genomic imprinting.

Hypervariable minisatellite DNA is found near the telomere and at other chromosome locations. Satellite 1 and alpha satellite DNA are found at the centromeres. Microsatellite DNA is dispersed throughout all the chromosomes. A nucleotide consists of a nitrogenous base, a sugar, and a phosphate group. Nitrogenous Bases 1. Purines a. Adenine A b. Guanine G 2. Pyrimidines a. Cytosine C b. Thymine T c. Uracil U , which is found in RNA 3. Base Pairing. Adenine pairs with thymine or uracil A-T or A-U.

Cytosine pairs with gua- nine C-G. Deoxyribose, which is found in DNA 2. Ribose, which is found in RNA C. Double Helix DNA. The DNA molecule is two complementary polynucleotide chains or DNA strands arranged as a double helix, which are held together by hydrogen bonding between laterally opposed base pairs bps. DNA can adopt different helical structures, which include: The most fundamental unit of packaging of DNA is the nucleosome. Histones are small proteins containing a high proportion of lysine and arginine that impart a positive charge to the proteins, which enhances its binding to negatively charged DNA.

Histone proteins have exposed N-terminal amino acid tails that are subject to modifica- tion and are crucial in regulating nucleosome structure. Histone acetylation of lysine by histone acetyltransferases HATs and histone deacetylation by histone deacetylases HDACs are the most investigated histone modifications. Histone acetylation reduces the affinity between histones and DNA.

An increased acetyla- tion of histone proteins will make a DNA segment more likely to be transcribed into RNA and hence any genes in that DNA segment will be expressed i. The 10 nm nucleosome fiber is joined by H1 histone protein to form a 30 nm chromatin fiber.

During interphase of mitosis, chromosomes exist as 30 nm chromatin fibers organized as extended chromatin Note: The extended chromatin can also form secondary loops. During metaphase of mitosis, chromatin undergoes compaction. A centromere is a specialized nucleotide DNA sequence that binds to the mitotic spindle during cell division.

A centromere is associated with a number of centromeric proteins, which include: Chromosomes have a single centromere that is observed microscopically as a primary con- striction, which is the region where sister chromatids are joined. During prometaphase, a pair of protein complexes called kinetochores forms at the cen- tromere and one kinetochore is attached to each sister chromatid. Microtubules produced the by centrosome of the cell attach to the kinetochore called kine- tochore microtubules and pull the two sister chromatids toward opposite poles of the mitotic cell.

Heterochromatin is condensed chromatin and is transcriptionally inactive. In electron micro- graphs, heterochromatin is electron dense i. An example of heterochromatin is the Barr body, which can be seen in interphase cells from females, which is the inactive X chromosome.

Constitutive heterochromatin is always condensed i. Facultative heterochromatin can be either condensed i. When chromatin is tran- scriptionally active, there is weak binding to the H1 histone protein and acetylation of the H2A, H2B, H3, and H4 histone proteins. Biochemistry of DNA. B Diagram depicting the chemical structure of the various components of DNA.

C Diagram of a DNA polynucleotide chain. DNA packaging. A Diagram depicting the various levels of packaging of double helix DNA found within a metaphase chromosome. Nucleosomes are pulled together by histone H1 to form a 30 nm diameter fiber. The 30 nm fiber exists either as extended chromatin or as secondary loops within a condensed metaphase chromosome.

C Compaction of DNA in a chromosome. The double helix DNA of a chromo- some is shown unraveled and stretched out measuring 88, um in length. During metaphase of mitosis, chromatin can become highly compacted. For example, human chromosome 1 contains about ,, bp.

The distance between each base pair is 0. So that, the physical length of the DNA comprising chromosome 1 is 88,, nm or 88, um ,, X 0. During metaphase, all the chromosomes condense such that the physical length of chromosome 1 is about 10 um.

Consequently, the 88, um of DNA comprising chromosome 1 is reduced to 10 um, resulting in an 8,fold compaction. In humans, the female is functionally 3. The nitrogenous bases that make up the hemizygous due to X chromosome inactiva- nucleotides of DNA are listed in which one of tion.

The inactivated chromosome is thus the following? A deoxyribose and ribose A satellite 1 DNA B deoxyribose, ribose, and phosphate B beta-satellite DNA C adenine, thymine, cytosine, uracil C facultative heterochromatin D adenine, thymine, cytosine, guanine D constitutive heterochromatin E euchromatin 4.

Which one of the following is a major component of centromeric DNA? Which one of the following is the way matin, facultative heterochromatin, bases are paired in a double helix of DNA? Both copies of the X chromosome in females are active only for a short time early in development. Double helix DNA is coiled around histones that are organized into nucleosomes, which form the extended chromatin that compacts into a metaphase chro- mosome.

A DNA nucleotide consists of one of the nitrogenous bases adenine, thymine, cytosine or guanine, the sugar deoxyribose, and a phosphate group. Uracil and the sugar ribose are components of RNA nucleotides. In RNA, adenine pairs with uracil U. Chromosome replication occurs during S phase of the cell cycle and involves both DNA syn- thesis and histone synthesis to form chromatin. The timing of replication is related to the chromatin structure.

An inactive gene packaged as het- erochromatin is replicated late in S phase e. An active gene packaged as euchromatin is replicated early in S phase e.

However, in other cell types e. Replication is described as semiconservative which means that a molecule of double helix DNA contains one intact parental DNA strand and one newly synthesized DNA strand. Chromosome replication begins at specific nucleotide sequences located throughout the chromosome called replication origins.

Normally, the S phase of the mammalian cell cycle is 8 hours. DNA helicase recognizes the replication origin and opens up the double helix at that site, forming a replication bubble with a replication fork at each end. The stability of the replication fork is maintained by single-stranded binding proteins.

A replication fork contains a: Okazaki fragments end when they run into a downstream RNA primer. The anti-neoplastic drugs camptothecins e. The anti-microbial drugs quinolones e. The kb TTAGGG n array is preceded by kb of telomere— associated repeats before any unique sequence is found.

The telomere allows replication of linear DNA to its full length. This problem of lagging strand shortening is solved by a special RNA-directed DNA poly- merase or reverse transcriptase called telomerase which has a RNA and protein component. Thus, the lagging strand is lengthened.

DNA ligase joins the repeats to the lagging strand and a nuclease cleaves the ends to form double helix DNA with flush ends. Telomerase is NOT utilized by a majority of normal somatic cells, so that chromosomes nor- mally get successively shorter after each replication; this contributes to the finite lifespan of the cell.

Telomerase is utilized by stems cells and neoplastic cells so that chromosomes remain per- petually long. Telomerase may play a clinical role in aging and cancer. Chromosomal breakage refers to breaks in chromosomes due to sunlight or ultraviolet irra- diation, ionizing irradiation, DNA cross-linking agents, or DNA damaging agents.

These insults may cause depurination of DNA, deamination of cytosine to uracil, or pyrimidine dimer- ization, which must be repaired by DNA repair enzymes. The normal response to DNA damage is to stall the cell in the G1 phase of the cell cycle until the damage is repaired. Some the components of BASC include: The clinical importance of DNA repair enzymes is illustrated by some rare inherited diseases that involve genetic defects in DNA repair enzymes such as xeroderma pigmentosa XP , ataxia-telangiectasia, Fanconi anemia, Bloom syndrome, and hereditary nonpolyposis col- orectal cancer.

Types of DNA damage include: This is the most frequent type of lesion and leaves the deoxyribose sugar-phos- phate with a missing purine base. Deamination of cytosine to uracil. About cytosines C per day are spontaneously deaminate to uracil U. If the U is not corrected back to a C, then upon replication instead of the occurrence of a correct C-G base pairing and U-A base pairing will occur instead.

Pyrimidine dimerization. Sunlight UV radiation can cause covalent linkage of adjacent pyrimidines forming for example, thymine dimers. Replication fork. This site is called a replication bubble RB. At both ends of a replication bubble a replication fork RF forms. DNA synthesis occurs in a bidirectional manner from each RF arrows. B Enlarged view of a RF at one end of the replication bubble.

C DNA syn- thesis on the lagging strand proceeds differently than on the leading strand. Finally, DNA ligase joins all the Okazaki fragments together. Human cells have a finite lifespan and this 3. Which one of the following is an accurate contributes to the aging process. Stem cells statement regarding chromosome replication? The reason for these observations is B It occurs during G1 in the cell cycle.

The chromosomes in stem cells and neo- 4. The leading strand of DNA in the replica- plastic cells do not generally shorten with tion fork is synthesized by which one of the each cell division.

The enzyme utilized by following mechanisms? B discontinuously by DNA polymerase delta. C DNA ligase D topoisomerase 5. The autosomal recessive disease Fanconi E telomerase anemia is characterized by chromosome breakage and rearrangements and most indi- 2. Some antineoplastic drugs act by inhibit- viduals with the disease will develop some ing which of the following?

The other enzymes are involved in the replication process in general, but it is telomerase that can recognize the TTAGGG telomere sequence to that it can be replicated. Many antineoplastic drugs act by inhibiting DNA replication. Chromosome replication occurs during the S phase of the cell cycle. Active genes are replicated early in S and inactive genes late in the S phase. Replication is semiconservative because there is one intact parental strand in a double helix of DNA and a newly synthesized strand.

In Fanconi anemia, DNA damage goes unrepaired and eventually reaches a point where the chromosome is unstable. The result is that there is chromosome breakage with rearrangements of chromosomal material. When a break occurs in a tumor suppressor gene, or proto-oncogenes are activated by chromosome rearrangements, the development of a malignancy is likely. In autosomal dominant inheritance: The disorder is observed in an equal number of females and males who are heterozygous for the mutant gene.

The characteristic family pedigree is vertical in that the disorder is passed from one gener- ation to the next generation. Transmission by the mother or father i. Although homozygotes for some autosomal dominant disorders do occur, they are rare because homozygosity for an autosomal dominant disorder is generally a genetic lethal. Genetic Risk Assessment. The genetic risk associated with an autosomal dominant disorder is as follows: Example 1.

Affected heterozygous mother and normal homozygous father: In autosomal dom- inant disorders, the affected parent is usually a heterozygote because homozygosity for an autosomal dominant allele is frequently a genetic lethal where those with the disorder die before they reproduce.

All possible combinations of alleles from the parents are shown in a Punnett square below. Example 2.

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Affected heterozygous mother and affected heterozygous father: In some autoso- mal dominant disorders e. The parents may actually be more concerned about the chances of having a child with normal stature than one with achondroplasia.

As mentioned above, homozygosity for an autosomal dominant allele is frequently a genetic lethal so that both parents with achondroplasia would be heterozygous. Example 3. Affected homozygous mother and normal homozygous father: In some autosomal dominant disorders e. This sit- uation is exceedingly rare and would most likely occur in cases of consanguinity, where the parents are related. If the parents of the proband are normal, the risk to the siblings of the proband is very low but greater than that of the general population because the possibility of germ line mosaicism exists.

New Mutations. In autosomal dominant disorders, new mutations are relatively common. In these cases, there will be an affected child with no family history of the disorder.

Germ line mosaicism is the presence of more than one cell line in the gametes in an otherwise normal parent and is the result of a mutation during the embryonic development of that parent. There is an increased risk for a new dominant mutation in fathers over 50 years of age. Reduced Penetrance. In a reduced penetrance, many individuals have the disorder mutation but do not develop disorder symptoms.

However, they can still transmit the disorder to their offspring. Variable Expressivity. In variable expressivity, the severity of the disorder can vary greatly between individuals.

Some people may have such mild disorder that they do not know they have it until a severely affected child is born. Marfan syndrome whereby a parent is tall and has long fingers, but one of his children is tall, has long fingers, and has serious car- diovascular defects. Pleiotropy refers to a situation when a disorder has multiple effects on the body. Marfan syndrome whereby the eye, skeleton, and cardiovascular system may be affected. Locus heterogeneity. In locus heterogeneity, genes at more than one locus may cause the dis- order.

Osteogenesis imperfecta whereby collagen a-1 I chain protein and colla- gen a-2 I chain protein are encoded by the COL1A1 gene on chromosome 17q A mutation in either gene will cause osteogenesis imperfecta.

Example of an Autosomal Dominant Disorder. Noonan Syndrome NS. NS is an autosomal dominant genetic disorder caused by mutations in the following genes: The PTPN11 gene on chromosome 12p This is an extracellular protein that plays a key role in the cellular response to growth factors, hormones, and cell adhesion molecules. This protein plays a key role in the signal transduction pathway for epidermal growth factor EGF action.

This protein plays a key role in the signal transduction pathway for receptor tyrosine kinase action. Many NS individuals have de novo mutations. In simplex cases i. In autosomal recessive inheritance: The disorder is observed in an equal number of females and males who are homozygous for the mutant gene. The characteristic family pedigree is horizontal in that the disorder tends to be limited to a single sibship i.

Mother and father each transmit a recessive allele to their sons or daughters. Both parents are obligate heterozygous carriers whereby each parent carries one mutant allele and is asymptomatic unless there is uniparental disomy or consanguinity, which increases the risk for autosomal recessive disorders in children. The genetic risk associated with an autosomal recessive disorder is as follows: Normal heterozygous mother and normal heterozygous father: In autosomal recessive disorders, both parents are carriers of a single copy of the responsible gene.

In autosomal recessive disorders, one can calculate the genetic risk for the normal chil- dren being homozygous or heterozygous. All the possible combinations of alleles from the parents are shown in a Punnett square below. Affected homozygous mother and normal heterozygous father: Example of an Autosomal Recessive Disorder. Cystic Fibrosis CF. The H2O maintains the mucus in a wet and less viscous form. The poly T tract is a string of thymidine bases located in intron 8 with the 5T, 7T, and 9T the most common variants.

Sweat chloride test. The pilocarpine iontophoresis for sweat chloride is the primary diag- nostic test for CF. In X-linked dominant inheritance: The disorder is observed in twice the number of females than males unless the disorder is lethal in males; then the disorder is observed only in females. Father-to-son transmission does not occur because males have only one X chromosome i. Males usually die a genetic lethal. Heterozygous females are mildly to overtly affected never clinically normal depending on the skew of the X chromosome inactivation.

Homozygous females double dose are overtly affected. The genetic risk associated with an X-linked dominant disorder is as follows: Affected heterozygous mother and normal father. In this example, the mother has the disorder XDX and the father is normal XY because X-linked dominant disorders are usually lethal in males. Normal mother and affected father. Examples of X-Linked Dominant Disorders. Hypophosphatemic rickets XLH. Classic Rett syndrome CRS. CRS is an X-linked dominant genetic disorder caused by various mutations in the MECP2 gene on chromosome Xq28 for methyl-CpG-binding protein 2 MECP2 which has a methyl-binding domain binds to 5-methylcytosine rich DNA and a transcription repression domain recruits other proteins that repress transcription.

Although MECP2 protein is expressed in all tissues and seems to act as a global transcriptional repressor, mutations in the MECP2 gene result in a predominately neurological phenotype.

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CRS is caused by missense, nonsense, small deletion, and large deletion mutations. Most mutations in the MECP2 gene occur de novo. In X-linked recessive inheritance: The disorder is observed only in males affected homozygous females are rare.

The characteristic family pedigree shows skipped generations representing transmission through female carriers. Males are usually sterile. Heterozygous females are clinically normal but may be mildly affected depending on the skew of the X chromosome inactivation.

The genetic risk associated with an X-linked recessive disorder is as follows: Affected homozygous mother and normal father: In this example, the mother has the disorder XrXr and the father is normal XY. Normal heterozygous mother and normal father: In this example, the mother is a carrier XrX and the father is normal XY.

Normal mother and affected father: If the father has an X-linked recessive disor- der, the chances of having any children is very low because X-linked recessive males usu- ally are sterile. However, there are a few cases of fertile X-linked recessive males.

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In this example, the mother is normal XX and the father has the disorder XrY. Example 4. Normal heterozygous mother and affected father: In this example, the mother is a carrier XrX and the father has the disorder XrY. This may occur in rare cases e. Example of X-Linked Recessive Disorder. The DMD gene is the largest known human gene. DMD is caused by small deletion, large deletion, deletion of the entire gene, duplication of one of more exons, insertion, or single-based change mutations.

Serum creatine phosphokinase CK measurement. Skeletal muscle biopsy. A skeletal muscle biopsy shows histological signs of fiber size vari- ation, foci of necrosis and regeneration, hyalinization, and deposition of fat and connec- tive tissue. Immunohistochemistry shows almost complete absence of the dystrophin protein. Males have one X chromosome and are therefore constitutively hemizygous but females have two X chro- mosomes. This is called clonal selection and means that all females are mosaics comprising mixtures of cells in which either the XM or XP is inactivated.

X-linked Dominant Inheritance. In X-linked dominant inheritance, heterozygous females are mildly to overtly affected never clinically normal. Why are heterozygous females mildly to overtly affected? If the X chromosomes with the normal recessive gene are inactivated in a large number of cells, the female will have a large number of cells in which the one active X chromosome has the abnormal dominant gene XD.

Therefore, the heterozygous female will be mildly to overtly affected i. Can a female ever show overt signs of an X-linked dominant disorder?

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The answer is YES. An X-linked dominant disorder may also be observed in females who inherit both X chromo- somes with the abnormal gene i. In this case, the heterozygous car- rier mother and the affected father pass on the X chromosome with the abnormal gene. This used to be an extremely rare event, but with the advances in treatment, more males affected with X-linked dominant disorders are surviving to reproductive age.

So, the prob- ability of inheriting an abnormal X chromosome from an affected father is increasing. X-linked Recessive Inheritance. In X-linked recessive inheritance, heterozygous females are for the most part clinically normal. Can heterozygous females ever show signs of an X-linked recessive disorder? If the X chromosomes with the normal dominant gene are inactivated in a large num- ber of cells, the female will have a large number of cells in which the one active X chromo- some has the abnormal recessive gene Xr.

Therefore, the heterozygous female will be mildly affected i.

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Can a female ever show overt signs of an X-linked recessive disorder? An X-linked recessive disorder may also be observed in females who inherit both X chromo- somes with the abnormal gene i. In this case, the heterozygous carrier mother and the affected father pass on the X chromosome with the abnormal gene. This used to be an extremely rare event, but with the advances in treatment, more males affected with X-linked recessive disorders are surviving to reproductive age.

So, the proba- bility of inheriting an abnormal X chromosome from an affected father is increasing. A A prototype family pedigree and explanation of the various symbols. B Pedigree of autosomal dominant inheritance. The characteristic family pedigree is vertical in that the disorder is passed from one generation to the next gener- ation. C Pedigree of autosomal recessive inheritance. The characteristic family pedigree is horizontal in that affected individuals tend to be limited to a single sibship i.

D Pedigree of X-linked dominant inheritance. The disorder is observed in twice the number of females than males. There is no father- to-son transmission. All daughters of an affected man will be affected because all receive the X chromosome bearing the mutant gene from their father.

All sons of an affected man will be normal because they receive only the Y chromosome from the father. E Pedigree of X-linked recessive inheritance. The disorder is observed only in males affected homozy- gous females are rare. There is no father-to-son transmission. Selected photographs of Mendelian inherited disorders. A Noonan syndrome. Photograph shows a young boy with Noonan syndrome. See text for various physical features.

B,C,D Cystic fibrosis. B Light micrograph shows a bronchus that is filled with thick mucus and inflammatory cells arrow. Smaller bronchi may be completely plugged by this material. C PA radiograph shows hyperinflation of both lungs, reduced size of the heart because of pulmonary compression, cyst formation, and atelecta- sis collapse of alveoli in both lungs.

D CT scan shows dilated, thick-walled bronchi large arrow , collapse of the right middle lobe small arrows which contains dilated airways A. E,F,G Hypophosphatemic rickets. E Photograph shows a young girl with typical bowing of the legs. F Radiograph shows typical bowing of the legs, near-normal mineralization of the bones, and pronounced widening of the epiphyseal growth plates medially at the knees arrows.

G Light micro- graph shows a wide epiphyseal growth plate where the chondrocytes in the zone of proliferation do not form neatly arranged stacks but instead are disorganized into irregular nests. H Rett syndrome. Photograph shows a 5-year-old girl with the typical hand position characteristic of this disorder. I Photograph shows a young boy with pseudohypertrophy of the calves.

Note how the boy braces himself by grabbing onto nearby fur- niture with his left hand. These patients are often late walkers. J Light micrograph shows fibrosis of the endomysium arrows surrounding the individual skeletal muscle cells.

K Light micrograph shows the replacement of skeletal muscle cells by adipocytes arrows in the later stages of the disorder, which causes pseudohypertrophy. L Light micrograph immunofluorescent staining for dystrophin shows intense staining at the periphery skeletal muscle cells from a normal individual.

In an individual with Duchenne muscular dystrophy, there would be complete absence of dystrophin staining. M Radiograph shows the typical appearance of a dilated cardiomyopathy with a water-bottle configuration and dilata- tion of the azygous vein arrow.

Which of the following is the risk that an 5. In X-linked recessive lethal disorders, the unaffected full sibling of a patient with cystic mutant gene is not always inherited from a fibrosis CF carries a mutated CF gene?

What approx- A 1 in 2 imate percentage of affected males is attrib- B 1 in 4 utable to a new mutation? Which of the following best I describes why this can happen? A year-old boy is referred to a genetics III clinic to rule out neurofibromatosis 1. What is the risk that the child of a mother has started getting lumps and bumps on his with cystic fibrosis will be a carrier of the dis- skin since he hit puberty. During the family ease?

He remembers 4. Which pedigree best represents X-linked that his brother had some birthmarks, but dominant inheritance for a nonlethal condi- not nearly as many as he has. He does not tion? This is an example of which of the fol- A autosomal dominant lowing? In Marfan syndrome, the affected protein, Fibrillin-1, is active in three parts of the The following pedigree applies to questions body: John 9.

Sally has a paternal uncle with hemo- A autosomal dominant philia B, an X-linked recessive disease. Her B autosomal recessive risk of having a child with hemophilia B is C X-linked dominant best described as which of the following? Britney and Kevin have two healthy sons, Preston and Jaden.

Britney has a full brother, The cause of this is which of the ciency.

Britney is currently 10 weeks preg- following? Blaine also has hemophilia A. Alan and his wife Annette have 2 children, How are Barbara and Blaine related? Bart and Barbara. Barbara has a daughter, A first cousins Cassie, and a son Chip.

Cassie and Blaine are B first cousins once removed married and have a son, Daniel, with hemo- C second cousins philia A. They are now expecting fraternal D second cousins once removed twins, a boy and a girl. Fragile X syndrome is one of the most This phenomenon is called: Because he is unaffected, there are 3 possible independent outcomes. He now has a 1 in 3 chance of not carrying a mutated CF gene, but a 2 in 3 chance of being a carrier of a CF mutation.

The mother is homozygous for a CF mutation aa so she can only pass along a mutated gene a. The father is presumably homozygous for the normal gene AA , so he can only pass on a normal gene A. Therefore, all their children will be heterozygotes Aa , or carriers of a CF mutation. In Pedigree C, the condition appears in every generation in both sexes. In lethal disorders, all the mutated genes are lost in each generation and these represent a third of the alleles for that mutated gene.

Because different genes loci can be involved in the development of leukemia, there is locus heterogeneity. Neurofibromatosis 1 NF1 is an autosomal dominant disease with vari- able expressivity. The family history and the clinical findings in the patient confirm the diagnosis of NF1. One of the parents would probably be found to have some mild manifestation of the disease upon examination, as it is fully penetrant.

Pleiotropy is when a gene mutation produces diverse phenotypic events. Marfan syndrome is one of the best examples of pleiotropy. Achondroplasia is an autosomal dominant disease.

There is no family history because achondroplasia is often caused by a new mutation. G6PD deficiency is X-linked. Therefore, the risk for Sally to have a child with hemophilia B is near 0. Because Joe is unaffected, he can be a carrier or not be a carrier. He has a 1 in 3 chance of not being a carrier and a 2 in 3 chance of being a carrier. If sufficient numbers of normal X chromosomes are inactivated, there may not be enough of the normal gene product present for proper functioning.

The mutation could not have come from Blaine because he cannot pass on his X chromosome to his son. Both Barbara and Cassie are obligate carriers. Because Blaine has hemophilia A, he can only pass on an X chromosome with the mutation. Cassie is an obligate carrier with one X chromosome carrying the muta- tion and a normal X chromosome. The female fraternal twin can either receive a mutated X chromosome from both parents and have hemophilia A, or receive the mutated X from Blaine and a normal X from Cassie and be a carrier.

Blaine can only pass on a Y chromosome to sons. Cassie can either pass on the X chromosome with the mutation and her son will have hemophilia A, or pass on the normal X chromosome, in which case her son would be normal and not affected with hemophilia A.

In Fragile X syndrome the triplet repeat expansion, CGG, must reach a certain number of repeats before there is clinical manifestation of the disease. The repeat expands with succeeding generations and eventually will reach the critical number. That is why males without the disease can pass it on to subsequent generations where it appears because the threshold number of repeats has been reached.

Females with a high number of repeats may also express some manifestations of the disease because of skewed X inacti- vation. Myotonic dystrophy is caused by a triplet repeat expansion that expands with each succeeding generation. The larger the repeat, the earlier the onset and the more severe the disease is.

This phenomenon is called anticipation and differs from incomplete penetrance and variable expressivity in that once the critical repeat threshold is reached, the disease is manifested with severity depending on the number of repeats. If one copy is an identical copy of one homolog of a chromosome from a parent, then this is called isodisomy.

If the parent passes on both homologs of a chromosome, then this is termed heterodisomy. In both cases, the child does not receive a copy of that chromosome from the other parent. UPD can also be caused when a gamete with two copies of a chromosome combines with a gamete with no copies of that chromosome. UPD can be a causative factor in a number of disorders as indicated below. Because these syndromes are mostly due to a microdeletion on chromosome 15, they are discussed in Chapter However, UPD can cause the syndromes because the involved region is under control of genomic imprinting.

Genomic imprinting is where the expression of a gene or genes depends on the parent of origin. BWS can be caused by UPD where there is an excess of paternal material or loss of maternal material at chromosome 11p Autosomal recessive disorders.

In some cases, autosomal recessive disorders can be caused by UPD. Although this is a rare occurrence, UPD should be considered when only one parent is a carrier. For example, CF is an autosomal recessive disease, so both copies of the allele must have a mutation for the disease to be manifested.

Dynamic mutations are mutations that involve the expansion of a repeat sequence either out- side or inside the gene. Dynamic mutations represent a new class of mutation in humans for which there is no coun- terpart in other organisms.

The exact mechanism by which dynamic mutations occurs is not known. Although dynamic mutations may occur during mitosis resulting in mosaicism, dynamic mutations often occur only during meiosis producing the female or male gametes. Threshold Length. Dynamic mutations demonstrate a threshold length. Below a certain thresh- old length, the repeat sequence is stable, does not cause disease, and is propagated to succes- sive generations without change in length.

Above a certain threshold length, the repeat sequence is unstable, causes disease, and is propagated to successive generations in expanding lengths. Dynamic mutations demonstrate anticipation. Anticipation is one of the hall- marks of diseases caused by dynamic mutations.

Premutation Status. A normal person may have certain number of repeats that have a high likelihood of being expanded during meiosis i.

Most of dynamic mutation diseases are caused by expansion of trinucleotide repeats, although longer repeats do play a role in some diseases. Dynamic mutations are divided into two categories: This category of dynamic mutations is characterized by the following clinical conditions. Fragile X syndrome involves two mutation sites. They are stably transmitted without any decrease or increase in repeat number.

They are not stably transmitted. Fragile X syndrome is the second leading cause of inherited mental retardation Down syndrome is the number one cause. A longstanding hypothesis is that FRDA is a result of mitochondrial accumulation of iron, which may promote oxidative stress injury.

Myotonic Dystrophy Type 1 DM1. A hypothesis is that DM1 is caused by a gain-of-function RNA mechanism in which the alternate splicing of other genes e. A child with severe DM1 i. Because CAG codes for the amino acid glutamine, a long tract of glutamines polyglutamine tract will be inserted into the amino acid sequence of the protein and cause the protein to aggregate within certain cells. Huntington Disease HD. Because CAG codes for the amino acid glutamine, a long tract of glutamines a polyglutamine tract will be inserted into the Huntington protein and cause protein aggregates to form within certain cells such as implicated in other neurodegenerative disorders.

Premutation HD alleles have 27 to 35 repeats. Individuals with permutation HD alleles are at risk for having children with HD. A child with HD inherits the expanded repeat from the father. The dis- order is protracted and invariably fatal. In HD, homozygotes are not more severely affected by the disorder than heterozygotes, which is an exception in autosomal dominant disorders. A hypothesis is that SBMA is caused by a gain-of-function mutation because there is a well-known syndrome called complete androgen insensitivity that is caused by a loss-of- function mutation in the AR gene.

Premutation AR alleles have not been reported to date. SBMA occurs only in males. A hypothesis is that SCA3 is caused by impaired protein clearance because mutant ataxin 3 forms nuclear inclusions that contain elements of the refolding and degradation machinery of the cell i. Premutation ATXN3 alleles have not been reported to date. The prevalence of SCA3 in not known. Using a system based on genetic loci, numerous autosomal dominant ataxias have been classified SCA and the numbers continue to grow.

In general, all autosomal dominant ataxias are rare. Uniparental disomy.

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A Maternal nondisjunction produces an ovum with no copies of a specific chromosome and paternal nondisjunction produces a sperm with two copies of the same chromosome. After fertilization, the zygote has no copies of the maternal chromosome and two copies of the paternal chromosome. B Maternal nondisjunction pro- duces an ovum with two copies of a specific chromosome and paternal nondisjunction produces a sperm with no copies of the same chromosome. After fertilization, the zygote has two copies of the maternal chromosome and no copies of the paternal chromosome.

C Maternal disjunction produces an ovum with one copy of a specific chromosome and paternal nondisjunction produces a sperm with two copies of the same chromosome. After fertilization, the zygote has three copies of the same chromosome i.

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Promocode will not apply for this product. BRS Genetics addresses a field that is increasingly taught in shorter courses. Chapters are written in an outline format and include pedagogical features such as bolded key words, tables, algorithms, and numerous illustrations, including a page full-color insert.

A companion Website includes a question bank as well as fully searchable text. Table of contents. The Human Nuclear Genome 2. DNA Packaging 3. Chromosome Replication 4.