Genetic Chimerism: Marmosets contain multitudes
Single-cell RNA sequencing reveals the extent to which marmosets carry genetically distinct cells from their siblings.
- Center for Evolution and Medicine, School of Life Sciences, Arizona State University, United States
Marmosets almost always produce non-identical twins which, unusually, share much more than just a womb. The same circulatory system connects the siblings during pregnancy, allowing two genetically distinct individuals to freely exchange the hematopoietic stem cells that give rise to all blood and immune cells (Gengozian et al., 1969; Wislocki, 1939; Hill, 1932). As a result, a drop of blood from this tiny South American primate reveals a mixture of cells originating from each twin (Benirschike and Brownhill, 1962). This is known as sibling chimerism – from Chimera, the monster from Greek mythology that is a hybrid of a lion, a goat and other creatures.
This quirk of nature has been known for decades (Benirschke et al., 1962). Yet, while studies have detected genetic information from the other twin in certain organs, it has remained difficult to precisely test whether sibling chimerism is limited to blood-related cells or extends to other cell types (Sweeney et al., 2012; Ross et al., 2007). Answering this question would help to uncover how cellular exchange takes place between marmoset twins, while also allowing researchers to investigate how genetic variations affect cell function in vivo. However, this requires technology that has only become recently available, and which makes it possible to isolate and sequence the genetic material of individual cells in a single tissue. If different genomes are identified in a heart sample, for example, these newer approaches can now distinguish whether they originate from the muscle cells of the heart, the blood cells pumped through it, or the resident immune cells that protect it. Now, in eLife, Ricardo del Rosario, Steven McCarroll and colleagues at Harvard Medical School, the Broad Institute and MIT report having addressed this knowledge gap by applying single-cell sequencing to various marmoset organs (del Rosario et al., 2024).
Rather than focusing on DNA, the team took advantage of the thousands of genetic variants transcribed into RNAs and opted instead for single-nucleus RNA-sequencing. Being able to capture all the genes being transcribed in an individual cell did double duty. del Rosario et al. could identify which tissues contained cells from the other twin; and they could also examine the impact of these genetic differences on gene expression patterns and cell function.
To investigate the first question, the team tested for sibling chimerism in the blood, liver, kidney and brain – all tissues which contain varying amounts of cell types deriving from hematopoietic stem cells. This confirmed that chimerism is prevalent and widespread in marmosets, while also allowing del Rosario et al. to precisely identify which cells were from the sampled individual, and which were from its twin. In doing so, they demonstrated that sibling chimerism is limited to cells from the two lineages (myeloid and lymphoid) that hematopoietic stem cells give rise to. Across the organs studied, all the other cell types examined originated from the twin being sampled (Figure 1).
Figure 1
Investigating sibling chimerism in marmosets.
Marmosets almost always produce non-identical twins (also known as fraternal or dizygotic twins). However, these siblings are more alike than expected because they share a circulatory system in the womb, which allows them to exchange hematopoietic stem cells. As a result, the tissues and organs of the adult twins can contain cells carrying the genetic information of their sibling (orange cells in the yellow individual, and vice versa). Single-nucleus RNA sequencing approaches allowed del Rosario et al. to investigate which tissues contained cells from both twins, and in which proportion. This showed that only cells derived from hematopoietic stem cells display such ‘sibling chimerism’. In the brain, for example, the team found evidence for this phenomenon primarily in just one type of cell – immune cells known as microglia – with other cell types (such as neurons) being solely from the individual sampled.
The team then turned its attention to microglia, the primary immune cells of the brain, using a single-nucleus RNA-sequencing dataset of more than 2.2 million cells from various brain regions of 11 marmosets (Krienen et al., 2023). Consistent with the findings for non-brain tissues, this analysis first revealed that the proportion of sibling-derived microglia varies between the brain areas of an individual. del Rosario et al. suggest two possible explanations for this finding: (1) Such variations may be due to cell migration and proliferation taking place in a random manner, with the level of sibling-derived cells reflecting which cells arrived first and multiplied the most in a tissue. (2) Alternatively, cells from the twin may be recruited and proliferate differently across brain tissues and even local environments due to their genetic background.
To then test if genetic variations between cells could indeed impact their expression patterns, del Rosario et al. directly compared how microglia in the same brain region expressed their genes depending on whether they were from the sampled animal or its twin. When assessing if cells facing the same constraints respond differently because of variations in their genomes, this is as environmentally controlled a study can get in a living animal – nature’s very own common garden experiment, where scientists examine how populations of different genetic origins fare when facing the same conditions. The results show that the local environment, such as which brain region the cells were in, had a much larger impact in shaping gene expression than the genetic background. This does not indicate that genetic variation is unimportant, but it does highlight how cells – no matter who they come from – are very good at doing their job when they find themselves in the right place at the right time.
All told, this thoughtful and thorough study accomplishes two important goals. First, it all but closes a previously open question on the extent and cell origins of sibling chimerism. Second, it sets the stage for using this unique model system to examine, in a natural context, how genetic variation in microglia may impact brain development, function, and disease.
References
-
Further observations on marrow chimerism in marmosetsCytogenetics 1:245–257.https://doi.org/10.1159/000129734
-
The developmental history of the primatesPhilosophical Transactions of the Royal Society of London. Series B 221:45–178.https://doi.org/10.1098/rstb.1932.0002
-
Observations on twinning in marmosetsAmerican Journal of Anatomy 64:445–483.https://doi.org/10.1002/aja.1000640305
Article and author information
Author details
Noah Snyder-Mackler
Publication history
Copyright
© 2024, Chiou and Snyder-Mackler
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 392
- views
-
- 30
- downloads
-
- 0
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Genetic Chimerism: Marmosets contain multitudes
eLife 13:e97866.
https://doi.org/10.7554/eLife.97866
Further reading
-
- Genetics and Genomics
- Microbiology and Infectious Disease
Schistosoma mansoni is a parasitic flatworm that causes the major neglected tropical disease schistosomiasis. The miracidium is the first larval stage of the life cycle. It swims and infects a freshwater snail, transforms into a mother sporocyst, where its stem cells generate daughter sporocysts that give rise to human-infective cercariae larvae. To understand the miracidium at cellular and molecular levels, we created a whole-body atlas of its ~365 cells. Single-cell RNA sequencing identified 19 transcriptionally distinct cell clusters. In situ hybridisation of tissue-specific genes revealed that 93% of the cells in the larva are somatic (57% neural, 19% muscle, 13% epidermal or tegument, 2% parenchyma, and 2% protonephridia) and 7% are stem. Whereas neurons represent the most diverse somatic cell types, trajectory analysis of the two main stem cell populations indicates that one of them is the origin of the tegument lineage and the other likely contains pluripotent cells. Furthermore, unlike the somatic cells, each of these stem populations shows sex-biased transcriptional signatures suggesting a cell-type-specific gene dosage compensation for sex chromosome-linked loci. The miracidium represents a simple developmental stage with which to gain a fundamental understanding of the molecular biology and spatial architecture of schistosome cells.
-
- Genetics and Genomics
- Microbiology and Infectious Disease
Klebsiella pneumoniae is a global public health concern due to the rising myriad of hypervirulent and multidrug-resistant clones both alarmingly associated with high mortality. The molecular mechanisms underpinning these recalcitrant K. pneumoniae infection, and how virulence is coupled with the emergence of lineages resistant to nearly all present-day clinically important antimicrobials, are unclear. In this study, we performed a genome-wide screen in K. pneumoniae ECL8, a member of the endemic K2-ST375 pathotype most often reported in Asia, to define genes essential for growth in a nutrient-rich laboratory medium (Luria-Bertani [LB] medium), human urine, and serum. Through transposon directed insertion-site sequencing (TraDIS), a total of 427 genes were identified as essential for growth on LB agar, whereas transposon insertions in 11 and 144 genes decreased fitness for growth in either urine or serum, respectively. These studies not only provide further knowledge on the genetics of this pathogen but also provide a strong impetus for discovering new antimicrobial targets to improve current therapeutic options for K. pneumoniae infections.
