XX chromosome in male: The case of sex reversal

The XX chromosome in male: A case of sex reversal

You heard it right. I am talking about the XX chromosome in a male. XX chromosomes are universally present in a female. However, not frequent but XX chromosome may present in a male. In this article, we will discuss the rarest type of genetic defect which is uncommon in nature. 

The role of the XX chromosome in sex reversal is my research topic and our team was working on it since 2014. Guess what, we finally got some outstanding results. We reported two cases of 46, XX male. Read the article till last and you will discover something new today.


The XX male is phenotypically male but genotypically female having  the wide spectrum of congenital abnormalities.


In today’s article, we will talk about the role of the XX chromosome and XY chromosome in sex development, mechanism of sex reversal, the complication in XX males and related consequences.

I will briefly introduce the topic because our research paper is still not published, it is under review. But I will definitely explain each sub-topic in depth. 

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Sex chromosomes

The X Chromosome and Y chromosomes are called sex chromosomes. Apart from 22 pairs of autosomal chromosomes, XX chromosomes are present in female and XY chromosomes in the male. However, the XX chromosome does not play any significant role in sex development, Yet it is more significantly involved in sex determination.

The Y chromosome is responsible for the differentiation of sex. If Y chromosome in inherited into the developing embryo, it develops into male otherwise female. The SRY gene, Sex determination region present on Y chromosome which is present within TDF region is the candidate gene responsible for the maleness. The testis-determining factor on the Y chromosome (TDF) has all the genes and sequences which ultimately decides the fate of the embryo.



If the SRYgene expressed higher during embryogenesis ultimately it favours in testicular differentiation. However, some other autosomal genes such as SOX9, SOX3, FGF, WT1, WNT4 and NR0B1 also plays a crucial role in sex determination and differentiation.

Read more about the SOX9 gene in my review article: Genetics of Eunuchs: A review.

Yet, the exact role of each gene is still unclear and not explained by science. SOX9 comes out as another candidate gene for sex development. Studies have confirmed that SOX9 is second most candidate gene in the development of sex.

The X chromosome has several sequences present on the terminal ends of the both XX chromosomes which mimic like an autosomal region and hence it is called as pseudoautosomal region.

This pseudoautosomal region present on X chromosome involved in sex reversal mechanism. Both X chromosomes have the same type of genes. So the problem with the XX chromosome is the duplication of gene expression. 

The genes present on the X chromosome in a female may express twice higher as compared to male. To overcome this problem the cells developed a unique mechanism called as an X chromosome inactivation.

One X chromosome remains inactive during gene expression and ultimately, the gene expression level remains under control. Still, the PAR (pseudoautosomal region)  has the capacity to express because it mimics like an autosome.

The Y chromosome is smaller as compared to X chromosomes and has all the essential gene sequences which require for deciding the sex. However, the PAR region present on the Y chromosome is the same as in the female X chromosome. The PAR region on the Y chromosome in situated near the TDF region.

Mechanism of sex differentiation

Sex determination and differentiation is a complex process involving many autosomal genes along with SRY. It started at intermediate mesoderm where WT1, SF1 and DAX1 gene begins the sex development process and the urogenital ridge is created from the intermediate mesoderm.

The urogenital ridge ( euro– urinary system, genital-genital/ reproductive system) forms the bipotential gonad in which WT1, GATA4, SOX9 and DMRT1 genes expressed. Here the bipotential gonad has the capacity to develop into male or female.

XX chromosome in male: The case of sex reversal
The image represents the role of different genes during sex differentiation. Image © Tushar Chauhan.

At this stage of embryogenesis, if SRY is expressed, the bipotential gonad develops testis otherwise if not expressed it develops into an ovary. The process of switching on or off of the SRY gene expression is arbitrary. Yet, autosomal genes have an influence on SRY gene expression.

This is the actual process of sex development. But in some cases, the uncontrolled translocation, replication and gene expression dysregulates the entire process. and an individual may develop several DSD (Disorders of sex).

Mechanism of sex reversal

The entire story of sex reversal starts at the stage of spermatogenesis. Exchange of genetic material, called as recombination, is not possible between Y chromosome and X chromosome but the PAR region present on both chromosomes facilitates the recombination between the X chromosome and Y chromosome.

Recombination and translocation are possible between PAR region. The pseudoautosomal region characterized into PAR1 and PAR2 present on both ends of the chromosome recombinate during embryogenesis. The genes present within PAR region translocates as like autosomal chromosomes.

During the process of recombination (which is not naturally occurred between the X chromosome and Y chromosome) some regions of SRY gene translocates to X chromosome along with PAR. The SRY gene located within the TDF, are present near the PAR1 region of the Y chromosome, therefore, some sequences of SRY may transfer to X.

Now the whole story of sex reversal is originated from here. The entire SRY or partial SRY regions translocate on X called as “46, XX chromosome testicular DSD”. The condition is denoted as SRY+ 46, XX male.

XX chromosome in male: The case of sex reversal
The image represents the exchange of PAR region between the X chromosome and Y chromosome along with some portion of SRY. © Genetic Education Inc

Due to the exchange of genetic material testicular development begun in embryo having XX chromosome. However, the X chromosome also has genes for ovarian development. Therefore, testicular and ovarian both types of tissues are developed into the XX male. In addition, the genes involved in normal sex development are likewise confused and their activity is dysregulated as well.

Yet, the story does not end here, if the SRY gene segments are not translocated; deletion, duplication or translocation of autosomal genes involved in sex differentiation may induce XX male development. The condition is called as SRY– XX male sex reversal.

Candidate genes such as SOX9 and SOX3 plays an influential role in sex reversal. I found some mutation on SOX9 in XX male which I will discuss after the publishing of our research paper.

Ultimately, the individual having XX chromosome (male) suffer from the testicular disorders. The individual may have mixed genitalia having hypospadias, micropenis, clitoromegaly and other internal genital abnormality. Further, infertility is common in 46, XX male.

Some individuals behave like a female and have a higher level of female hormones. Broadly, the condition cannot be characterised into any categories of disorder because of the wide spectrum of phenotypic abnormalities.

It is a rare congenital abnormality found approximately 1 in 20,000 to 25,000 male worldwide. The condition cannot be inherited hence do not follows Mendelian inheritance. However, the individual with 46, XX testicular DSD is sterile, cannot reproduce.

We found some of the outstanding results during our study, I have published an article on this topic. You can download it here, Genetics of Eunuchs: A review. Download it and read it.

XX chromosomes do not play a vital role in sex development Yet, it is very essential in sex determination. I am very excited about ongoing research at the life science research foundation. Last night my colleague had shared result telephonically to me so I thought, I have to share it with my readers.

I will definitely share all the information regarding 46, XX male later. Stay connected with this topic.

Further, read our article here, Genetics of Eunuchs: A review and do visit our research centre here, life science research foundation (LRF), Gujarat.

If you have any information about the role of the XX chromosome in sex development please share with us.

Article written by: Tushar Chauhan

Article reviewe by: Binal Tailor



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