Seminario 14 Cromosomas sexuales y herencia - Rodolfo Rey

Introduction to Sex Chromosomes and Inheritance

Overview of the Seminar

• Rodolfo Rey introduces the seminar focusing on sex chromosomes, X chromosome inactivation, and inheritance linked to X and Y chromosomes.

• The class plan includes a review of sex chromosomes, their behavior during mitosis and meiosis, and detailed discussions on X chromosome inactivation.

Characteristics of Sex Chromosomes

• Humans have 23 pairs of chromosomes; 22 are autosomes while the last pair consists of sex chromosomes (XX for females, XY for males). Exceptions exist.

• The X chromosome is significantly larger than the Y chromosome, containing approximately 164 megabases compared to 60 megabases in the Y chromosome. It also has more genes: 867 on X versus only 55 on Y.

Meiosis and Genetic Exchange

Differences Between Autosomes and Sex Chromosomes

• Unlike autosomes that can exchange genetic material freely during meiosis through homologous recombination, sex chromosomes can only do so at specific pseudoautosomal regions (PAR1 and PAR2).

• These pseudoautosomal regions allow for genetic exchange similar to autosomes; however, most parts of the X and Y chromosomes do not undergo this exchange under normal conditions.

Genetic Anomalies

• In abnormal conditions, there may be exceptions where genetic material can be exchanged outside these regions leading to anomalies such as XX males carrying SRY gene from Y chromosome. This results in atypical sexual differentiation outcomes.

Genes on Sex Chromosomes

Key Genes on the Y Chromosome

• The small size of the Y chromosome limits its gene count; notable genes include SRY (testicular determination) and TSPI (linked to gonadoblastoma development). Other genes relate to spermatogenesis but are less understood.

Genes Specific to the X Chromosome

• The X chromosome contains over 800 unique genes that are expressed primarily from one copy due to inactivation of most regions except for some areas including PAR1 and PAR2 which escape this process. Thus about 15% - 20% remain active across both copies during female development.

Cell Division Mechanics

Behavior During Mitosis

Meiosis and Gamete Formation

Overview of Meiosis

• Meiosis occurs in the terminal cells of ovaries and testes, specifically in oocytes and spermatocytes, leading to the formation of gametes.

• A diploid cell contains two homologous chromosomes (one maternal and one paternal), which duplicate their DNA during the S phase, resulting in sister chromatids.

First Meiotic Division

• During the first meiotic division, homologous chromosomes pair up and undergo crossing over, leading to genetic recombination.

• The result is cells with 22 autosomes and one sex chromosome that contain double the amount of genetic material but with exchanged segments from both parents.

Developmental Differences Between Males and Females

• In fetal life, spermatogonia multiply by mitosis while oocytes begin meiosis, forming primary oocytes that pause until puberty.

• In males, meiosis starts at puberty; unlike females where it begins during fetal development but halts until later stages.

Chromosome Behavior During Meiosis

• Male meiosis results in secondary spermatocytes followed by spermatids that mature into spermatozoa without further cell division.

• Sex chromosomes only pair in pseudoautosomal regions during meiosis. This pairing allows for proper segregation despite size differences between X and Y chromosomes.

Genetic Exchange Mechanisms

• Each secondary spermatocyte will have either an X or a Y chromosome along with duplicated autosomes after the first meiotic division.

• The second meiotic division yields haploid spermatids with either an X or a Y chromosome, some containing exchanged genetic material from pseudoautosomal regions.

Oocyte Development Process

• Oocyte development mirrors male processes but begins earlier; all resulting ovum will carry an X chromosome potentially having undergone genetic exchange.

• Genetic exchange occurs similarly across homologous chromosomes in females as it does in males due to their homology.

Implications for Offspring Genetics

• Males contribute either an X or a Y chromosome through sperm while females always provide an X chromosome via ova.

• The sex of offspring is determined by whether a sperm carrying an X or Y fertilizes the egg; thus, maternal contribution is always an X for XX individuals.

Inactivation of One X Chromosome

Inactivation of the X Chromosome: Key Concepts

Understanding Dosage Compensation in XX and XY Individuals

• Individuals with a 46XX karyotype have two doses of most genes located on the X chromosome, while those with a 46XY karyotype have only one dose since these X-specific genes are absent from the Y chromosome.

• It might be expected that individuals with two active X chromosomes would produce double the amount of RNA and protein from these genes; however, this is not observed due to X-inactivation.

The Process of X-Inactivation

• The phenomenon known as "X-inactivation" was described by Mary Lyon in the 1960s, where one X chromosome in each somatic cell of females becomes inactive, leading to dosage compensation between genders.

• This process results in equal gene product levels (RNA and protein) from the X chromosome across both males (46XY) and females (46XX).

Characteristics of X-Inactivation

• Randomness: In an XX individual, either the paternal or maternal X can be randomly inactivated in different cells, resulting in a mosaic pattern where some cells express one allele while others express another.

• Fixation: Once an X chromosome is inactivated within a cell, all daughter cells will maintain that same inactive status for that specific chromosome.

Mosaicism and Cytogenetic Manifestations

• Normal females exhibit two distinct cellular populations due to mosaicism—one expressing an active paternal X and another expressing an active maternal X.

• Cytogenetically, this can be observed through Barr bodies (or sex chromatin), which represent the inactive X chromosome visible during metaphase.

Implications for Different Karyotypes

• In typical 46XX females, Barr bodies are present due to one active and one inactive X. Conversely, individuals with Turner syndrome (45X karyotype) lack Barr bodies because there is only one active X.

• Triple-X syndrome (47XXX karyotype) results in two Barr bodies as two out of three chromosomes are inactive.

Exceptions to Random Inactivation

• In extraembryonic tissues like placentae, paternal alleles are always chosen for inactivation rather than being random.

• Germline cells such as oocytes retain both copies of the X chromosome as active without undergoing any form of inactivation.

Mechanism Behind Inactivation

• The initiation occurs at a region called the "X-inactivation center," located on the long arm of the X chromosome at position Q13. This region contains essential genes involved in regulating this process.

Inactivation of the X Chromosome and Its Implications

Mechanism of X Inactivation

• The long non-coding RNA, known as "ist," is involved in the inactivation of one X chromosome in females, which is not present in males due to their lack of an inactive X chromosome.

• This RNA remains within the nucleus and coats the inactive X chromosome, recruiting proteins that inhibit transcription across most of the chromosome.

• The process leads to condensation of the inactive chromosome, forming structures like Barr bodies or sexual chromatin.

Phenotypic Effects of Extra X Chromosomes

• Individuals with additional X chromosomes (e.g., Klinefelter syndrome) exhibit distinct phenotypic characteristics compared to typical male or female individuals despite having some inactivated chromosomes.

• Differences persist because not all regions undergo complete inactivation; some genes remain active even when extra chromosomes are present.

Random and Incomplete Inactivation

• The random nature of X inactivation means that either paternal or maternal chromosomes can be silenced, leading to a mosaic pattern across different cells.

• Approximately 15% to 20% of genes on the X chromosome escape this inactivation, resulting in double dosage expression for those genes.

Growth Implications from Gene Expression

• Genes escaping inactivation can lead to increased expression levels; for instance, individuals with Klinefelter syndrome may have taller stature due to excess growth-related gene activity.

• Specifically, a gene called "Shocks" contributes to growth when expressed excessively due to its location outside the regions subject to inactivation.

Genetic Disorders Linked to X Inactivation

• GPR143 is a gene linked with ocular albinism when mutated; it shows random mosaicism based on which allele is active or inactive within retinal pigment cells.

• Variants affecting this gene result in varying melanin production depending on whether normal or mutated alleles are expressed.

Understanding X-linked Diseases

• Common belief states that X-linked diseases are transmitted by females and affect males. However, inheritance patterns can show variability based on carrier status among females and affected males.

Genetic Inheritance and X-Linked Disorders

Understanding Genetic Variants

• The discussion begins with the importance of identifying amino acid variants at specific positions, such as cysteine and tyrosine at position 235, to understand normal versus pathogenic genetic variants.

X-Linked Inheritance Patterns

• A genealogical example illustrates that a healthy male can be a carrier of a variant on the X chromosome, which he passes to his daughters, leading them to develop primary ovarian failure despite him being unaffected.

Mechanisms of Genetic Transmission

• The objective is for students to grasp the underlying mechanisms of genetic diseases rather than just memorizing mnemonics. This includes understanding how traits are transmitted from parents to offspring.

Defining X-Linked Disorders

• Diseases linked to the X chromosome arise from altered DNA sequences on this chromosome. These can be classified into recessive or dominant inheritance patterns similar to autosomal disorders.

Recessive vs Dominant X-Linked Conditions

• Recessive conditions manifest when an individual lacks a normal allele on their active X chromosome. Conversely, dominant conditions appear if there is an abnormal allele present in either an XY or XX genotype.

Illustrative Examples of Genetic Disorders

• An example involving the vasopressin receptor gene located on the long arm of the X chromosome (XQ28) highlights its role in kidney function and how mutations lead to nephrogenic diabetes insipidus, characterized by excessive urination.

Family Genetics and Carrier Status

• A family tree analysis shows potential outcomes for children when one parent is a carrier for an X-linked disorder. Daughters may become carriers while sons inherit their father's Y chromosome and could express the disease if they receive a mutated allele from their mother.

Genetic Inheritance Patterns in X-Linked Disorders

Overview of X-Linked Inheritance

• The offspring from a carrier mother will have a 50% chance of being healthy carriers and a 50% chance of being healthy non-carriers.

Case Study: Affected Father with Healthy Non-Carrier Mother

• An example is presented where the father has a mutation in the BPR2 gene on the X chromosome, leading to nephrogenic diabetes insipidus. The mother is healthy and not a carrier.

• Sons inherit the normal Y chromosome from their father and an unaffected X chromosome from their mother, resulting in both being healthy non-carriers. Daughters inherit one affected X chromosome from their father and one normal X chromosome from their mother, making them heterozygous carriers but not affected by the disease.

Implications of X-Linked Disorders

• It is noted that while typically women transmit these disorders, in this case, it is the father who suffers due to his condition. This highlights exceptions in typical inheritance patterns for X-linked diseases.

Descendants' Health Outcomes

• All male descendants (46XY) are healthy non-carriers, while all female descendants (46XX) are healthy carriers due to inheriting one affected allele from their father and one normal allele from their mother. This differs significantly from previous examples discussed.

Rare Cases: Affected Male with Carrier Female

• The discussion shifts to rarer cases where an affected male marries a carrier female, often seen in small endogamous communities where consanguinity occurs. This scenario can lead to different inheritance outcomes compared to more common cases.

Genetic Transmission Dynamics

• Males pass on the unaffected Y chromosome to sons and the affected X chromosome to daughters; females can pass either an affected or unaffected X chromosome to both sons and daughters, complicating potential health outcomes for offspring.

Potential Outcomes for Offspring

• Daughters may be homozygous or compound heterozygous depending on whether they inherit identical mutations or different ones; males can be either affected or unaffected based on which alleles they receive from parents. This complexity illustrates that not all inherited conditions follow straightforward patterns as previously assumed.

Analysis of Genetic Testing Results

• When genetic testing reveals no abnormalities in karyotyping but identifies a deletion within exon 3 of the ABPR2 gene through sequencing, it indicates specific mutations affecting protein function (loss of histidine). Both parents’ genetic contributions are analyzed for understanding inheritance patterns further.

Family Genetic Analysis Findings

• The analysis shows that while both father and son exhibit symptoms of diabetes insipidus, they do not share identical mutations; this emphasizes how complex genetic inheritance can be when considering multiple alleles across generations.

The son inherits his father's Y chromosome instead of his mutated X chromosome due to standard inheritance rules for males.

Additionally, maternal analysis reveals discrepancies between expected alleles indicating possible new mutations or variations present only in certain family members rather than shared across all descendants.

This underlines challenges faced during genetic counseling regarding familial risk assessments based solely on traditional Mendelian models without considering unique family genetics dynamics at play here.

Genetic Analysis of X-Linked Traits

Understanding Alleles in Female Siblings

• The first sister is a carrier with one mutated allele from the father and one normal allele from the mother, making her a healthy carrier.

• The second sister has two mutated alleles (one from each parent), indicating she is affected by the condition. This suggests a larger deletion beyond just three base pairs.

Heterozygosity and PCR Techniques

• The affected sister is classified as a compound heterozygote due to having different mutations on both alleles, while the unaffected sister is simply heterozygous.

• PCR (Polymerase Chain Reaction) can amplify specific DNA sequences; however, it may not detect small deletions effectively but can identify larger ones that do not amplify at all.

Limitations of PCR in Genetic Detection

• A difference of three base pairs between amplified products may not be visually detectable on a gel, limiting PCR's effectiveness for minor variations. Larger deletions will result in no amplification, indicating their presence.

• To assess the extent of large deletions, alternative techniques like array CGH or MLPA are recommended for more detailed analysis beyond what PCR can provide.

Inheritance Patterns of X-Linked Traits

• X-linked recessive traits manifest when an individual lacks a normal allele on an active X chromosome; this applies to both males and females differently based on their genetic makeup.

• Males inherit their Y chromosome from their father and an X chromosome from their mother, which could either be normal or mutated, affecting offspring health outcomes accordingly. Females receive one normal X from their father and either a normal or mutated X from their mother, leading to varied carrier statuses among siblings.

Dominant vs Recessive X-Linked Disorders

• In contrast to recessive disorders, dominant X-linked conditions always manifest if there is at least one affected allele present; this includes conditions like hypophosphatemic rickets linked to mutations in the FEX gene located on the short arm of the X chromosome.

Genetic Disorders and Inheritance Patterns

Overview of Genetic Anomalies

• The discussion begins with the identification of low stature, dental anomalies, and low phosphate levels in blood due to renal loss of phosphate. This condition leads to decreased phosphate reabsorption in kidneys, resulting in lower blood phosphate levels.

Family Genetics Example

• A family example illustrates X-linked inheritance where a woman carries one normal X chromosome and one affected X chromosome. The male offspring receive a Y chromosome from their father and an X from their mother, which can be either normal or mutated.

Transmission Dynamics

• Male children will inherit the Y chromosome from their father and an X chromosome (normal or mutated) from their mother. Female children will inherit a normal X from their father and may receive either a normal or pathogenic variant X from their mother. This results in heterozygous females being affected by the dominant trait while homozygous females remain unaffected.

Disease Manifestation

• The disease discussed is not strictly following the common pattern where women transmit X-linked diseases to males; instead, it also affects females who carry the pathogenic variant. In this case, 50% of male offspring are expected to be affected while 50% remain healthy non-carriers among female offspring as well. Understanding these patterns requires reasoning rather than rote memorization.

BMP15 Gene Implications

• The BMP15 gene located on the short arm of the X chromosome plays a crucial role in ovarian folliculogenesis but has no significant role in males. Mutations lead to follicular atresia causing premature ovarian failure manifesting as delayed menstruation or lack thereof during puberty stages.

Offspring Outcomes Based on Parental Genotype

• In families where the affected allele comes from the father, all sons will be hemizygous for that gene (healthy), while daughters will be heterozygous carriers showing symptoms due to dominant inheritance patterns associated with only one affected allele being sufficient for disease manifestation. Thus, both daughters would exhibit symptoms despite receiving one normal allele from their mother.

Rare Cases of Y-linked Inheritance

• Transitioning to Y-linked inheritance patterns reveals that males inherit these traits directly from fathers leading to 100% affected male offspring while female offspring remain unaffected since they do not receive any Y chromosomes at all—highlighting rarity due to limited genes on Y chromosomes related primarily to testicular development and spermatogenesis which if mutated could lead to infertility thus preventing transmission through generations.

Diagnosis Methodology

• Diagnosis involves thorough phenotyping including patient history taking, physical examination, imaging studies, laboratory tests aimed at characterizing organ systems involved before moving onto genotyping methods such as karyotyping or microarray analysis for detecting numerical abnormalities or specific mutations within genes linked with observed conditions like hearing loss potentially tied back into genetic factors discussed earlier regarding chromosomal influences on health outcomes across generations.

Genetic Testing and Disease Associations

Overview of Genetic Testing Approaches

• The discussion begins with the importance of identifying structural anomalies in sex chromosomes, specifically X or Y chromosomes. If no significant abnormalities are detected through karyotyping, microarray analysis, or MLPA, the next step is DNA sequencing.

• When there is a high suspicion of a specific gene being involved in a disease, Sanger sequencing (single-gene techniques) is employed. Alternatively, if multiple genes may be potential causes for the condition, massive parallel sequencing (NGS) is utilized.

Distinction Between Sex-Linked Traits and Chromosomal Disorders

• It’s crucial to differentiate between traits or diseases associated with sex versus those linked to sex chromosomes. For example:

• Thyroid disorders are more prevalent in women but do not involve sex chromosomes.

• Hypertension and heart disease are more common in men without direct correlation to chromosome I or X.

Examples of Gender-Specific Diseases

• The speaker provides examples illustrating gender-specific prevalence:

• Breast cancer occurs more frequently in women.

• Prostate cancer has a higher incidence in men.