The Complete Human Y Chromosome Marks An Opportunity To Move Away From Stigma

For many years, the human Y Chromosome was terra incognita. Scientists completed the genetic sequences of other Chromosomes, the threadlike structures that hold an organism's DNA. But more than 50 percent of the Y chromosome remained unknown because of the challenges posed by its highly repetitive DNA.

Then, in August, the Y chromosome became the last human chromosome to be completely sequenced. This outstanding achievement reminds us of both the promises and perils of genomics research. The Y chromosome's completion caps a history of ideology and superstition about genetics and human behavior that is illustrative of how people can use genetics to dehumanize those viewed as "disabled."

The Y chromosome is mainly known for its role in sexual development. Most individuals who are assigned male at birth have a Y chromosome, though this does not singularly define a person's sex, and more recent Studies have found the Y chromosome plays additional roles in human health.

Since the Y chromosome's discovery in 1905, society has fixated on its significance far more intensely than that of any other chromosome, and has largely done so while operating in an absence of scientific knowledge. Throughout the 20th century, this fueled the development of a stigma that persists. Only by understanding this history—how the stigma was born of uncertainty, fear, simplifications of sex and gender and misguided beliefs about genetics and complex social behaviors—can we fully appreciate the fundamental importance of the complete Y chromosome sequence.

Early studies of the Y chromosome were tinged with eugenics. Some of the first studies of inheritance linked to this chromosome were conducted in 1922 by geneticist and eugenicist William E. Castle, who pointed to the inheritance of webbed toes as an example of a Y-linked trait. In the following decades, many other scientists ventured to connect the Y to an array of problematically framed human traits.

Proponents of eugenics obsessed over "subnormal" individuals, an ableist characterization of intellectual and developmental disability. From the 1930s through the 1990s, poorly founded studies reported that the Y chromosome was tied to intellectual disabilities. This swiftly led to the belief that individuals with two Y chromosomes were "subnormal," and over the years other social traits were unscientifically ascribed to these individuals.

Double Y syndrome, also known as Jacobs syndrome, was first observed  in 1961 and affects about 1 in 1,000 male individuals (this may be underreported because many people are unaware that they have additional sex chromosomes). XYY individuals were quickly dubbed "supermale," however, and simplistic views of sex, gender and masculinity helped form a spurious and stigmatizing image of people with double Y syndrome.

In the same era, many researchers searched for biological explanations for complex societal "dilemmas," such as the origins of violence and aggression. Some scientists supposed that aggression is natural, perhaps even "evolutionarily desirable," and therefore must have a genetic origin. When coupled with sexist beliefs that men are inherently aggressive, this led to routes of inquiry that tied aggression and violence to the Y chromosome.

Beginning with a handful of unscientific studies, most notably one described in a 1965 issue of Nature, researchers falsely connected double Y syndrome to violence and criminality. These conceptions were not only applied to people with additional Y chromosomes. Y chromosomes naturally vary in size among different individuals, and some researchers attempted to develop metrics based on the misguided assumption that a significantly physically larger Y chromosome was correlated to criminality and "antisocial behavior."

These studies lacked scientific rigor, relying on highly selective samples, such as those from maximum security correctional hospitals. They also ignored how "delinquency," as it was then called, largely grew from social and environmental conditions rather than genetics.

These unscientific and ableist speculations reached the American public in 1967, however, during the trial of Richard Speck, who was convicted of killing eight nurses in Chicago and was mistakenly reported as having double Y syndrome. In the coming decades, XYY murderers became a common plot device in books, movies and TV shows, such as in the 1993 Law & Order episode "Born Bad," in which a lawyer claims a 14-year-old boy cannot be held accountable for murder because he has double Y syndrome.

Despite the lack of scientific evidence, trusted institutions and figures promoted these ideas. In a 1968 Psychology Today article, celebrated anthropologist Ashley Montagu incorrectly, but forcibly, argued that "it appears probable that the ordinary aggressiveness of a normal XY male is derived from his Y chromosome." The National Institute of Mental Health's Center for Studies of Crime and Delinquency equivocated on the matter. In 1970, the center published a report that did not deny a connection between the XYY genotype and criminality, even though the same report cited clear evidence to the contrary and acknowledged other factors at play. Additionally, a 1974 report released by the National Institute of Neurological Diseases and Stroke contributed to these stereotypes of XYY individuals, even though "simple factual errors" were quickly pointed out, including in discussion of Richard Speck and his erroneously reported XYY genotype.

Many geneticists urged caution in this area, including Ernest B. Hook, who identified these errors. Others later added to the more scientifically robust studies that found no correlation between criminality and the Y chromosome. As early as 1970 the Lancet published a letter stating that there was "no evidence" of an association between double Y syndrome and criminality, and other researchers not long after stated categorically that genetic screening programs for additional Y chromosomes had "eugenic implications." Unscientific studies on the Y chromosome continued, however, and in the public eye, much damage was done.

The Y chromosome still holds a cultlike fascination. More recently, the news overflowed with studies on the loss of the Y chromosome, both as something that occurs within individuals as they age and as an evolutionary phenomenon. Some conversations around the Y chromosome's disappearance invoked words such as "degenerate"—a term with eugenic connotations. Others demonstrated how public discourse still treats the Y chromosome as an arbiter of masculinity. In anticipation of the Y chromosome's evolutionary disappearance—a prediction that relies on considerable speculation, without much scientific backing—discussions of "What will happen to men?" abound.

The complete Y chromosome sequence emerges against this backdrop. Not surprisingly, this sequence tells us nothing about complex social realities or the nature of "disability" or masculinity. The answers to such questions can't be found in a DNA sequence, regardless of its quality.

Instead the complete Y chromosome sequence offers many new scientific and clinical insights. This sequence will allow scientists to perform far more powerful genomics studies. Thus, we will be able to better understand how the Y chromosome contributes to areas of human health such as fertility and cancer.

Such studies won't change the existing stigma, however, especially because ableism persists throughout biomedical and behavioral research. As more studies launch from this new sequence, we must counteract this long history by confronting it head-on in both science and public understanding. The Y chromosome's sequence may be complete, but in reversing a long history of misinformation, we're only just getting started.

The views expressed by these authors do not reflect those of the National Institutes of Health, the Department of Health and Human Services or the U.S. Government.

This is an opinion and analysis article, and the views expressed by the author or authors are not necessarily those of Scientific American.

Karyotyping For Chromosomal Abnormalities

In order to maximize the diagnostic information obtained from a chromosome preparation, images of the individual chromosomes are arranged into a standardized format known as a karyotype, or more precisely, a karyogram (Figure 1a-c). According to international conventions, human autosomes, or non-sex chromosomes, are numbered from 1 to 22, in descending order by size, with the exceptions of chromosomes 21 and 22, the former actually being the smallest autosome. The sex chromosomes are generally placed at the end of a karyogram.

Within a karyogram, chromosomes are aligned along a horizontal axis shared by their centromeres. Individual chromosomes are always depicted with their short p arms—p for "petite," the French word for "small"—at the top, and their long q arms—q for "queue"—at the bottom. Centromere placement can also be used to identify the gross morphology, or shape, of chromosomes. For example, metacentric chromosomes, such as chromosomes 1, 3, and 16, have p and q arms of nearly equal lengths. Submetacentric chromosomes, such as chromosomes 2, 6, and 10, have centromeres slightly displaced from the center. Acrocentric chromosomes, such as chromosomes 14, 15, and 21, have centromeres located near their ends.

Arranging chromosomes into a karyogram can simplify the identification of any abnormalities. Note that the banding patterns between the two chromosome copies, or homologues, of any autosome are nearly identical. Some subtle differences between the homologues of a given chromosome can be attributed to natural structural variability among individuals. Occasionally, technical artifacts associated with the processing of chromosomes will also generate apparent differences between the two homologues, but these artifacts can be identified by analyzing 15–20 metaphase spreads from one individual. It is highly unlikely that the same technical artifact would occur repeatedly in a given specimen.

DNA Index Most Effectively Identifies Patients With Hyperdiploid ALL

The measure of total DNA in leukemic cells as defined by a DNA index outperformed other criteria for identifying patients with hyperdiploid acute lymphoblastic leukemia (ALL) and favorable prognosis.

Among several definitions, the measure of total DNA in leukemic cells defined by a DNA index (DI) showed the most efficacy in identifying patients with hyperdiploid acute lymphoblastic leukemia (ALL) in a study published in the Journal of Clinical Oncology.1

DNAImage credit: vitstudio - stock.Adobe.Com

ALL is the most common form of childhood cancer, and ALL with high hyperdiploidy—which refers to cells containing more chromosomes than usual—is the most common subgroup. ALL with hyperdiploidy carries a favorable prognosis relative to other subtypes, but hyperdiploidy has a varied biology, and different subgroups have shown different treatment responses.

"Although generally associated with excellent survival with most patients treated on a low-intensity regimen, there is a wide heterogeneity of biology across hyperdiploidy, with disparate treatment response and outcomes among subgroups," the authors wrote. "Although higher modal numbers of chromosomes are generally associated with a better prognosis, the exact chromosomal modal group with the best prognosis remains unclear."

Researchers at St. Jude Children's Research Hospital aimed to determine which of several definitions of hyperdiploidy in childhood ALL identifies patients with the best prognosis whose treatment could be deintensified. The relationship between hyperdiploidy and drug sensitivities was also explored in the study to see if these sensitivities happen in a chromosome-specific way.

"Hyperdiploidy is not monolithic. It is essential to identify the individual chromosome gains to better understand its effects. The gain of specific chromosomes can result in varying drug sensitivity and resistance," said co–corresponding author Jun J. Yang, PhD, departments of Pharmacy and Pharmaceutical Sciences and Oncology at St. Jude Children's Research Hospital, in a press release.2

The study evaluated 6 definitions of hyperdiploid ALL used by various cooperative study groups:

A total of 1096 patients were analyzed in the study, 915 of whom had B-cell ALL (B-ALL). The researchers also performed ex vivo pharmacotyping on 634 patients, 526 of whom had B-ALL, to investigate the relationship between hyperdiploidy and drug sensitivities.

A univariate analysis found that the most favorable criterion for event-free survival (EFS) and cumulative incidence of relapse (CIR) was TT when compared with other B-ALL cases, with a 10-year EFS of 97.3% vs 86.8% (P = .0003) and 10-year CIR of 1.4% vs 8.8% (P = .002).

The DI was the most favorable criterion in a multivariable analysis that factored in patient numbers using the Akaike information criterion (AIC) to determine which model was the best fit for the data set. It showed the best AIC for EFS (HR, 0.45; 95% CI, 0.23-0.88) and CIR (HR, 0.45; 95% CI, 0.21-0.99). Overall survival was assessed as a secondary end point, and the researchers noted similar trends.

"Taken together, DI was consistently the most significant prognostic factor in multivariable analysis; by contrast, Chr51-67, trisomy 18, and UK-ALL low-risk hyperdiploid group did not remain statistically significant after adjusting for clinical prognostic factors," the authors wrote.

Pharmacotyping showed that patients with hyperdiploid ALL and those in subgroups with favorable prognostic factors showed sensitivity to asparaginase and mercaptopurine. Trisomy of chromosomes 16 and 17 was associated with asparaginase sensitivity, and gains of chromosomes 14 and 17 were linked to mercaptopurine sensitivity.

"Hyperdiploidy definitions have historically been derived from the retrospective studies of previous protocols," said co–corresponding author Ching-Hon Pui, MD, departments of Oncology, Pathology, and Global Pediatric Medicine at St. Jude Children's Research Hospital.2 "By comprehensively comparing 6 different classification methods in the same patient cohort, we show that a simple system, such as the DNA index, is optimal for stratifying patients with a good prognosis. This approach remains applicable in modern studies with contemporary risk-directed therapies."

The authors concluded that the findings provide a foundation for determining the optimal definition for hyperdiploidy and align with increasing evidence that identifying specific prognostic chromosomes and those associated with drug resistance is key in this population.

References

1. Lee SHR, Ashcraft E, Yang W, et al. Prognostic and pharmacotypic heterogeneity of hyperdiploidy in childhood ALL. J Clin Oncol. Published online September 20, 2023. Doi:10.1200/JCO.23.00880

2. St. Jude refines definition and hones treatment of hyperdiploid leukemia. News release. St. Jude Children's Research Hospital. September 20, 2023. Accessed September 22, 2023. Https://www.Stjude.Org/media-resources/news-releases/2023-medicine-science-news/st-jude-refines-definition-and-hones-treatment-of-hyperdiploid-leukemia.Html