On average, only 10 % of the human population is left-handed. Interestingly, five out of the last nine American presidents have been left-handed: Barack Obama, Bill Clinton, George H. W. Bush, Ronald Reagan and Gerald Ford (approximately 55 %).
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This macro-scale human motor asymmetry has intrigued researchers for centuries. In ancient civilizations, including those of Greece, Rome, China, and Mesopotamia, right-handedness was prevalent, dominant, and revered. It was considered a privilege to sit to the right of someone.
In Latin, the word for left is "sinister," while the word for right is "dexter." Even in antiquity, these terms carried dual meanings of awkward and skillful, respectively.
Today, "sinister" has taken on an even more negative connotation. During the Middle Ages, being left-handed was deemed sinful and associated with the devil. During the Inquisition, mere left-handedness was sufficient to condemn a woman as a witch, leading to the execution of numerous innocent left-handed individuals.1
Researchers have long sought clues to this asymmetry, with some proposing that the greater mortality of left-handers in battles has contributed to the higher prevalence of right-handedness today.
Beyond myths, understanding handedness is also pertinent to understanding brain lateralization, and recent research indicates that this macro-scale asymmetry can be traced down to the molecular level.
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Right versus left-brain
The brain is divided into two hemispheres: the right and the left. Experiments and imaging demonstrate that the brain is "cross-wired," with movement on the left side of the body primarily controlled by the right hemisphere and vice versa. Furthermore, different regions of the brain are responsible for distinct functions.
Research from the 1960s characterized the left side of the brain as more logical and mathematical, while the right side was associated with creativity and emotion. However, more recent studies indicate that although each hemisphere has different specializations, there is extensive communication through the nerve fibers of the corpus callosum, allowing both halves to work collaboratively.
For example, the left hemisphere has traditionally been linked to processing mathematical equations; however, research shows that the right hemisphere also contributes to spatial awareness during complex calculations, understanding numbers with zeros, and representing numbers in a nonverbal manner.
Similarly, language processing has been attributed to the left brain, yet the right hemisphere plays a significant role in comprehending context and non-literal language, including metaphors and irony.
The importance of the right hemisphere in the emotional and contextual aspects of language may explain why left-handed individuals often excel as orators and are frequently found in successful political roles.
While it is tempting to categorize individuals as left-brained or right-brained, as creativity and logic are often perceived as opposites, the reality is far more nuanced.
Understanding left-handedness is more significant than merely defining personality types; gross motor lateralization may be part of molecular-based cues within a larger developmental framework.
Molecular handedness
As we look more closely at the human body, asymmetry reveals itself at every level. Major organs, such as the stomach and liver, are typically located on the left and right sides of the body, respectively, except in very rare instances.
Within specific organs, asymmetry is also evident, for example, the heart exhibits left-to-right asymmetry. Upon further examination, it becomes clear that most biomolecules are asymmetric or chiral.
Chirality refers to the three-dimensional molecular asymmetry that prevents a molecule from being superimposed on its mirror image. Chiral molecules can be categorized as left-handed or right-handed, with a clockwise spiral identified as right-handed.
Most DNA exists as right-handed double helices; imagine walking down a DNA staircase, where one would turn to the right. A molecule's handedness significantly influences its function.
For instance, nearly all organisms exclusively produce and metabolize left-handed amino acids while utilizing right-handed sugars, highlighting the importance of chirality in biological processes. Current research is uncovering the mechanistic connections between genetics and asymmetry at the cellular, organ, and organism levels.
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Is being left-handed genetic?
Research indicates that genetic, epigenetic, environmental, and social factors all contribute to handedness. Notably, while the proportion of left-handed individuals among twins aligns with that of the general population, studies have shown a higher concordance rate of handedness among monozygotic (identical) twins compared to dizygotic twins, suggesting a genetic influence on handedness.2
Initial Genome-Wide Association Studies (GWAS) faced challenges in identifying statistically significant genetic markers for left-handedness. However, advancements in biobanks have facilitated studies with larger population sizes, leading to statistically significant findings.
Recent GWAS studies have identified associations between left-handedness and microtubule-associated genes (e.g., TUBB, MAP2, and MAPT). Furthermore, a GWAS study analyzed brain imaging and genome sequencing data from over 32,000 UK Biobank participants and discovered 27 independent genetic variants significantly associated with structural brain asymmetry.
Nearly half of these loci were associated with genes that code for tubulins or microtubule-associated proteins. However, the majority of the regions fell outside of protein-coding genes and were instead involved in regulating gene expression.
A recent study based on exome data from over 350,000 individuals in the UK Biobank has also identified rare coding variants that may be linked to left-handedness.3
Difference between exome-wide and genome-wide association studies
The primary population-wide genomic methodologies for assessing genetic variation related to specific diseases or conditions include genome-wide association studies (GWAS), whole-genome sequencing (WGS), and whole-exome sequencing (WES).
GWAS typically involves targeted genotyping of pre-selected variants utilizing microarrays or selective sequencing. These studies can identify single nucleotide polymorphisms (SNPs) or structural variations within intronic or exonic regions of the genome.
WGS involves decoding the entire genome, while WES focuses specifically on sequencing only the exons—the coding regions of genes. Although the exome makes up just 1–2 % of the genome, it's estimated to account for roughly 85 % of the mutations identified in Mendelian diseases.4
Exome-wide studies are particularly useful for detecting rare variants, as they allow for greater sequencing depth at a similar cost.
Traditionally, whole-exome sequencing has been conducted on tissue samples; however, there is now a noticeable shift toward utilizing plasma and other bodily fluids. Analyzing plasma from a liquid biopsy is significantly less invasive than a tissue biopsy, and whole-exome sequencing of cell-free DNA (cf-DNA) from liquid biopsies has demonstrated the capability to uncover tumor-associated biomarkers and potential clues regarding the tissue of origin.5
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Whole-exome sequencing reveals a rare protein-coding variant associated with left-handedness
A recent study has also utilized the extensive resources of the UK Biobank to analyze exome data from 38,043 left-handed individuals and 313,271 right-handed individuals. The analysis identified rare coding variants in TUBB4B, a tubulin protein, which were found to be significantly more prevalent in left-handed individuals (2.7 times higher than in their right-handed counterparts).
Previous research has linked TUBB4B variants to sensorineural and ciliopathic disorders. Across the population studied, most TUBB4B variants were identified as heterozygous missense alterations.
Notably, this study observed two frameshift mutations occurring exclusively in left-handed individuals, both predicted to induce degradation of the TUBB4B RNA transcript through nonsense-mediated decay.
Consequently, these frameshift variants are anticipated to result in haploinsufficiency. Additionally, variants of two other genes, DSCAM and FOXP1, were associated with left-handedness, albeit with lower statistical significance. These genes warrant further investigation, as they have been previously implicated in autism and schizophrenia through exome screening.
While individuals carrying these rare coding variants are more likely to be left-handed, burden heritability analysis estimated the contribution of these variants to left-handed heritability at only 1 %.
Although the precise mechanism by which microtubules influence human handedness remains unclear, evidence suggests that microtubules may play a role in cellular chirality during early brain development, subsequently affecting the formation of the brain’s left-right axis.
Health implications of left-handedness
One study has indicated that left-handed individuals may face a slightly elevated risk of accidental injuries and death, likely due to the predominance of tools and devices designed for right-handed usage.6
Others have suggested that while left-handed attackers may possess an advantage by striking from the left side, left-handed defenders may be at a disadvantage, leading to a higher risk of injury in self-defense situations.
Although some research has proposed that left-handed individuals have shorter lifespans, more recent studies indicate that factors such as changing societal pressures, such as the historical coercion of left-handed individuals to switch to right-handedness, have influenced these findings.7
When models account for the increasing proportion of left-handed individuals over time, there is no significant difference in lifespan between left-handed and right-handed individuals. This increase in left-handedness over time also serves as a confounding factor in studies examining the effects of left-handedness on diseases that impact longevity.
There appears to be a notable association between left-handedness and certain psychotic disorders. Among patients with mental disorders, approximately 40 % of individuals with schizophrenia or schizoaffective disorder are left-handed, a figure four times higher than the prevalence of left-handedness in the general population.8
Transcriptomic and proteomic analyses have also revealed reduced expression levels of certain tubulin-associated genes (e.g., TUBA1B) and proteins in specific brain regions. However, individuals receiving treatment with antipsychotic medications did not exhibit lower levels of TUBA1B. These results contribute to the hypothesis that a disruption in cytoskeletal homeostasis may play a role in the development of schizophrenia.
This notion is further supported by research on clozapine, one of the few effective medications for schizophrenia, which directly binds to α and β tubulin heterodimers, inhibiting their polymerization during microtubule formation and disrupting the microtubule network.9,10
Recent research indicates that left-handed individuals face a heightened risk of cardiovascular disease (CVD).
Studies have demonstrated that left-handed individuals exhibit lower vascular endothelial function and an inverse relationship between artery dilation, specifically flow-mediated dilation (FMD), and mean arterial pressure. FMD refers to the widening of an artery in response to increased blood flow, and low FMD is a strong predictor of CVD.
In left-handed individuals, as mean arterial pressure rises, FMD decreases; conversely, right-handed individuals show no correlation, with FMD remaining stable across a range of arterial pressures.
While the overall impact of handedness on life expectancy remains a topic of debate, data suggests a higher prevalence of certain health conditions among left-handed individuals compared to their right-handed counterparts.11
Acknowledgments
Produced from material originally authored by Alison Waller.
References and further reading
- Milenkovic, S., et al. (2019). Historical aspects of left-handedness. Srpski arhiv za celokupno lekarstvo, (online) 147(11-12), pp.782–785. https://doi.org/10.2298/sarh190522095m.
- Pfeifer, L.S., et al. (2022). Handedness in twins: meta-analyses. BMC psychology, [online] 10(1), p.11. https://doi.org/10.1186/s40359-021-00695-3.
- Schijven, D., et al. (2024). Exome-wide analysis implicates rare protein-altering variants in human handedness. Nature Communications, (online) 15(1), p.2632. https://doi.org/10.1038/s41467-024-46277-w.
- Annaratone, L., et al. (2021). Basic principles of biobanking: from biological samples to precision medicine for patients. Virchows Archiv, (online) 479(2), pp.233–246. https://doi.org/10.1007/s00428-021-03151-0.
- Manier, S., et al. (2018). Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-04001-5.
- Baldwin, I., et al. (2021). Genomic, Clinical, and Behavioral Characterization of 15q11.2 BP1-BP2 Deletion (Burnside-Butler) Syndrome in Five Families. International Journal of Molecular Sciences, 22(4), p.1660. https://doi.org/10.3390/ijms22041660.
- Coren, S. (1989). Left-handedness and accident-related injury risk. American Journal of Public Health, 79(8), pp.1040–1041. https://doi.org/10.2105/ajph.79.8.1040.
- Webb, J.R., et al. (2013). Left-Handedness Among a Community Sample of Psychiatric Outpatients Suffering From Mood and Psychotic Disorders. SAGE Open, 3(4), p.215824401350316. https://doi.org/10.1177/2158244013503166.
- Snelleksz, M. and Dean, B. (2021). Lower levels of tubulin alpha 1b in the frontal pole in schizophrenia supports a role for changed cytoskeletal dynamics in the aetiology of the disorder. Psychiatry Research, (online) 303, p.114096. https://doi.org/10.1016/j.psychres.2021.114096.
- Hino, M., et al. (2021). Tubulin/microtubules as novel clozapine targets. Neuropsychopharmacology Reports, 42(1), pp.32–41. https://doi.org/10.1002/npr2.12221.
- Simon, A.B., et al. (2023). Evidence of increased cardiovascular disease risk in left-handed individuals. Frontiers in Cardiovascular Medicine, 10. https://doi.org/10.3389/fcvm.2023.1326686.
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