Lecture+06+Sex+Determination+and+Development+S22

Sex Determination and Development

Sex Determination: XX and XY

Biological sex, which refers to the classification as male or female, is established at the moment of conception when sperm fertilizes an egg, leading to the formation of either XX chromosomes for females or XY chromosomes for males. These sex chromosomes are classified as non-homologous, meaning they do not have corresponding partners, and they pair during the process of meiosis, which is essential for creating gametes (sperm and eggs).

Sexual Determination

Physical differences between genders start to become apparent around the 9th week of prenatal development. At approximately 5 weeks, the gonads (the organs that will develop into testes or ovaries) are still in a "bipotential" stage, meaning they have not yet specialized and can form either male or female reproductive systems.

There are two primary duct systems present during this early stage:

• Wolffian ducts: These will develop into male reproductive structures, such as the vas deferens and seminal vesicles.

• Mullerian ducts: These will develop into female reproductive structures, including the fallopian tubes and uterus.

At around week 6, the presence of the SRY gene (Sex-determining Region of Y chromosome) becomes crucial. This gene is found on the Y chromosome and is responsible for producing the Testis Determining Factor (TDF), which starts the process of male sex determination. TDF promotes the formation of testes and influences the development of other male reproductive structures. The gene SOX9, controlled by TDF, is vital for testis formation, while the gene Wnt4 inhibits SOX9 activity, leading to the formation of ovaries. Therefore, the presence of the SRY gene indicates male development, while its absence typically leads to female development.

Sex Chromosomes

The XX configuration in females is termed homogametic, as they possess two identical sex chromosomes, whereas XY males are referred to as heterogametic, having one of each type of sex chromosome. In some other species, like birds, there is a different system; for example, males are represented as ZZ and females as ZW. The X chromosome carries over 1,500 genes and is significantly larger than the Y chromosome, which has a much smaller gene set and is not homologous, yet it has functional similarities during meiosis.

Y Chromosome

The Y chromosome consists of two main regions:

• Pseudoautosomal regions (PAR1 and PAR2): These regions are homologous to the X chromosome and allow pairing and recombination during meiosis, which is crucial for genetic diversity.

• Male-specific region (MSY): This constitutes about 95% of the Y chromosome, is non-homologous with the X chromosome, and contains around 20 male-specific genes necessary for fertility. Some regions of the Y chromosome share similarities with X genes, while others lack counterparts required for testis development and fertility. It also includes sequences that can lead to replication errors, complicating genetic inheritance.

Sexual Development

The SRY gene plays a significant role as a transcription factor that kicks off male gonadal development. Hormones such as testosterone and dihydrotestosterone (DHT) are fundamental in the process of sexual differentiation. Sexual development is intricate and involves multiple steps; any excess of SOX9 can lead to disorders of sex development, disrupting the normal patterns of differentiation.

Hermaphroditism

Hermaphroditism describes organisms that possess both male and female reproductive structures. Intersex conditions may arise when there is a mismatch between internal and external reproductive organs. An example includes pseudohermaphroditism, where both male and female structures present at different life stages or developmental phases. One instance of this is 5-alpha reductase deficiency, where testosterone promotes internal male structures' growth, but a lack of DHT leads to insufficient external male characteristics. Another condition, Congenital adrenal hyperplasia (CAH), results in excessive testosterone and DHT, impacting the development of external genitalia, sometimes leading to ambiguous genitalia.

Sex Ratio

The sex ratio indicates the relative number of males compared to females in a population. Under Mendelian genetics, the expected ratio at conception is approximately 1:1. Typically, about 1,050 males are conceived for every 1,000 females. This changes slightly at birth, leading to a secondary sex ratio, and eventually by age 65 and older, the ratio adjusts to around 720 males per 1,000 females due to various factors including disease and mortality rates.

Sex-Linked Inheritance

Sex-linked inheritance pertains to traits that are associated with the X or Y chromosomes. Y-linkage is uncommon because there are relatively few genes on the Y chromosome. The higher number of X-linked genes can lead to specific illnesses or genetic disorders if mutated. Females have two copies of X-linked genes, making them diploid, whereas males are hemizygous, having only one X chromosome, which often means they exhibit recessive traits more frequently. Males inherit their sole X chromosome from their mother, with fathers not passing on X-linked traits to their sons.

Examples of X-Linked Disorders

• Ichthyosis: A recessive X-linked condition that primarily affects males, where females may be carriers but show no symptoms.

• Colorblindness: An X-linked recessive disorder caused by errors during recombination, leading to various forms of color vision deficiency, particularly involving opsin genes.

• Hemophilia B: Also known as Christmas disease, this is a deficiency of Factor IX, predominantly affecting males and inherited through X-linked recessive patterns; it has historical connections to royal families in Europe, specifically the lineage of Queen Victoria.

X-Linked Dominant Disorders

Disorders linked to X-linked dominant inheritance are rare and mainly arise from new mutations. These conditions often have severe effects in affected females and can be lethal in males, commonly preventing the transmission of the allele to the next generation. Incontinentia Pigmenti (IP) is a milder example that can be expressed in females but is often lethal in males.

Mendelian X-Linked Problems

When solving X and Y chromosome problems, alleles are denoted as superscripts to signify their genetic variants. For example, a problem involving Kallman syndrome may require evaluating the genotypes of individuals, such as Brenda, Jamal, and Malcolm, to determine inheritance probabilities.

Possible Outcomes

The likelihood of passing on genetic conditions like Kallman syndrome depends on whether Brenda is a carrier; calculating the odds of her son being affected may yield a 1 in 4 chance if she is indeed a carrier. Inheritance pathways based on genotypes provide insights into expected outcomes for offspring.

Solution

A sample calculation illustrating Kallman syndrome includes assessing genotypes and phenotypes, enabling predictions regarding the likelihood of genetic conditions based on parental genetics and gamete formation for potential offspring.

Sex-Limited Traits

Traits influenced by sex can impact structures or functions existing only in one sex, and they can be either autosomal or X-linked. Examples include genetic mutations that affect milk yield in dairy cows or alleles influencing facial hair growth in men.

Sex-Influenced Traits

Traits whose dominance fluctuates depending on the individual's sex can also be autosomal or X-linked. For instance, pattern baldness tends to be dominant in males but recessive in females, as hormonal differences influence the expression of these traits.

X-Inactivation

In females, one of the two X chromosomes undergoes a process called inactivation (around 75%) by the time the embryo reaches the 8-cell stage. This inactivation is random—either the paternal or maternal X chromosome can be inactivated—resulting in the formation of a Barr body. The regulatory RNA XIST is crucial in signaling X-inactivation, leading to a unique mosaic phenotype in heterozygous individuals. This process is classified as an epigenetic change and does not alter the underlying DNA sequence, and notably, this inactivation can be reversed in germline cells.

Phenotypes of X-Inactivation

The expression of traits linked to X-inactivation can vary in heterozygous individuals, notably regarding characteristics such as hair and skin color, as seen in calico cats. Disorders like hemophilia showcase different expression patterns in heterozygous females compared to males, highlighting the various presentations of symptoms associated with gender differences.