Christina M Laukaitis
- Associate Professor, Medicine
- Director, Division of Genetic Consultation and Counseling
- Assistant Professor, Cancer Biology - GIDP
- Assistant Professor, Genetics - GIDP
- Associate Professor, Nutritional Sciences
- Associate Professor, Pathology
- M.D. Medicine
- University of Illinois, Champaign-Urbana, Illinois, United States
- Ph.D. Cell and Structural Biology
- University of Illinois, Champaign-Urbana, Illinois, United States
- Mendel Medal Awardee
- Mendelianum of the Moravian Museum, Spring 2019
- American College of Medical Genetics, Spring 2015
- Researcher of the Year
- Arizona American College of Physicians, Fall 2013
- American Cancer Society Institutional Research Grant
- Institutional discretionary use of American Cancer Center funding (IRG-74-0013), Summer 2012
- Yellen Distinguished Young Investigator Award
- University of Arizona Cancer Center, Spring 2011
- Cancer Center Support Grant Developmental Funding
- Institutional discretionary use of National Cancer Institute funding, Spring 2009
No activities entered.
CBIO GIDP Seminar SeriesCBIO 596H (Fall 2020)
DissertationGENE 920 (Fall 2020)
Survey of Hum. Gen. DisordersCMM 622 (Fall 2020)
DissertationGENE 920 (Spring 2020)
CBIO GIDP Seminar SeriesCBIO 596H (Fall 2019)
ResearchGENE 900 (Fall 2019)
ResearchGENE 900 (Spring 2019)
CBIO GIDP Seminar SeriesCBIO 596H (Fall 2018)
Directed ResearchBIOC 392 (Spring 2018)
CBIO GIDP Seminar SeriesCBIO 596H (Fall 2017)
Directed ResearchBIOC 392 (Fall 2017)
ResearchGENE 900 (Fall 2017)
Honors ThesisMCB 498H (Spring 2017)
CBIO GIDP Seminar SeriesCBIO 596H (Fall 2016)
Honors ThesisMCB 498H (Fall 2016)
Honors Independent StudyECOL 299H (Spring 2016)
- Stopeck, A., Laukaitis, C. M., & Thompson, P. A. (2013). Breast cancer prevention. In Fundamentals of Cancer Prevention. Berlin, Germany: Springer-Verlag.
- Laukaitis, C. M., & Karn, R. C. (2012). Recognition of subspecies status in the evolution of incipient reinforcement on the European house mouse hybrid zone. In Evolution of the House Mouse. Cambridge, UK: Cambridge University Press.
- Lazarowitz, S. G., Ward, B. M., Sanderfoot, A. A., & Laukaitis, C. M. (1997). Intercellular and intracellular trafficking: What we can learn from Geminivirus movement. In Cellular Integration of Signalling Pathways in Plant Development. Berlin, Germany: Springer-Verlag.
- Jesudas, R., Chaudhury, A., & Laukaitis, C. M. (2019). An update on the new classification of Ehlers-Danlos syndrome and review of the causes of bleeding in this population. Haemophilia : the official journal of the World Federation of Hemophilia, 25(4), 558-566.More infoIt has long been hypothesized that bleeding symptoms in people with hypermobility occur as a result of abnormalities in the collagen of the vessel wall or the connective tissues. The bleeding symptoms, particularly in the skin, have been attributed to the fragility of skin and blood vessels caused by "defective collagen wickerwork" of the reticular layer of the skin. Collagen, which forms the framework of vessel walls, is altered in many patients with Ehlers-Danlos syndrome (EDS) leading to weakening of the vessel wall or the supporting tissues. Another important function of subendothelial collagen is its interaction with platelets and von Willebrand factor, which results in the propagation of a platelet plug. Thus, abnormalities in subendothelial collagen may alter its interaction with platelets and VWF. More recently, hypermobile-EDS (hEDS) has been associated with mast cell disorders, a condition independently associated with bleeding symptoms. It has also been observed that patients with mild bleeding disorders have a more severe bleeding phenotype when they have co-existing joint hypermobility.
- Laukaitis, C. M. (2018). International Mendel Days in the US/AZ. Folia Mendeliana, 54(1-2), 67-70.
- Tus, K., Harris, D. T., Lebeau, L., Laukaitis, C. M., Valori, V., & Maggert, K. (2019). Human rDNA Copy Number Is Unstable in Developing Breast Cancers. Epigenetics.
- Valori, V., Tus, K., Laukaitis, C., Harris, D. T., LeBeau, L., & Maggert, K. A. (2019). Human copy number is unstable in metastatic breast cancers. Epigenetics, 15(1-2), 85-106.More infoChromatin-mediated silencing, including the formation of heterochromatin, silent chromosome territories, and repressed gene promoters, acts to stabilize patterns of gene regulation and the physical structure of the genome. Reduction of chromatin-mediated silencing can result in genome rearrangements, particularly at intrinsically unstable regions of the genome such as transposons, satellite repeats, and repetitive gene clusters including the rRNA gene clusters (). It is thus expected that mutational or environmental conditions that compromise heterochromatin function might cause genome instability, and diseases associated with decreased epigenetic stability might exhibit genome changes as part of their aetiology. We find the support of this hypothesis in invasive ductal breast carcinoma, in which reduced epigenetic silencing has been previously described, by using a facile method to quantify copy number in biopsied breast tumours and pair-matched healthy tissue. We found that and satellite DNA sequences had significant copy number variation - both losses and gains of copies - compared to healthy tissue, arguing that these genome rearrangements are common in developing breast cancer. Thus, any proposed aetiology onset or progression of breast cancer should consider alterations to the epigenome, but must also accommodate concomitant changes to genome sequence at heterochromatic loci.
- David, T., Janousek, V., Laukaitis, C. M., Karn, R. C., Yazdanifar, G., & Flicek, P. (2018). Repeat associated mechanisms of genome evolution and function revealed by the Mus caroli and Mus pahari genomes. Genome Research, 28(4), 448-459.
- Huynh, J. M., Galindo, M., & Laukaitis, C. M. (2018). Missense variants in in a patient with Joubert syndrome. Clinical case reports, 6(11), 2189-2192.More infoWe present a patient with a clinical diagnosis of Joubert syndrome with COACH phenotype who carries two variants of uncertain significance (VUS). One VUS can be reclassified as "likely pathogenic" by adding clinical data. As genetic testing becomes more accessible, more VUS will require clinical correlation for accurate classification.
- Huynh, J., Galindo, M. K., & Laukaitis, C. M. (2018). Novel and Missense Variants of Uncertain significance in TMEM67 Present in a Patient With Joubert Syndrome. Molecular Case Studies, 6(11), 2189-2192.
- Chung, A. G., Belone, P. M., Bímová, B. V., Karn, R. C., & Laukaitis, C. M. (2017). Studies of an Androgen-Binding Protein Knockout Corroborate a Role for Salivary ABP in Mouse Communication. Genetics, 205(4), 1517-1527.
- Pezer, Z., Chung, A. G., Karn, R. C., & Laukaitis, C. M. (2017). Analysis of copy number variation in the Abp gene regions of two house mouse subspecies suggests divergence during the gene family expansions. Genome Biology and Evolution, 9(6), 1393-1405.
- Huynh, J. M., & Laukaitis, C. M. (2016). Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer. Molecular genetics & genomic medicine, 4(2), 232-6.More infoThe reported penetrance of germline CDH1 mutations is high in families with hereditary diffuse gastric cancer (HDGC). Men and women have a 70% and 56%, respectively, cumulative risk of developing diffuse gastric cancer by age 80. Women additionally have a 42% cumulative risk of developing breast cancer. Due to the high penetrance of these mutations, prophylactic total gastrectomy is currently recommended for CDH1 mutation carriers. However, whether everyone with a CDH1 gene mutation is at risk for HDGC is not clear.
- Janoušek, V., Laukaitis, C. M., Yanchukov, A., & Karn, R. C. (2016). The Role of Retrotransposons in Gene Family Expansions in the Human and Mouse Genomes. Genome biology and evolution, 8(9), 2632-50.More infoRetrotransposons comprise a large portion of mammalian genomes. They contribute to structural changes and more importantly to gene regulation. The expansion and diversification of gene families have been implicated as sources of evolutionary novelties. Given the roles retrotransposons play in genomes, their contribution to the evolution of gene families warrants further exploration. In this study, we found a significant association between two major retrotransposon classes, LINEs and LTRs, and lineage-specific gene family expansions in both the human and mouse genomes. The distribution and diversity differ between LINEs and LTRs, suggesting that each has a distinct involvement in gene family expansion. LTRs are associated with open chromatin sites surrounding the gene families, supporting their involvement in gene regulation, whereas LINEs may play a structural role promoting gene duplication. Our findings also suggest that gene family expansions, especially in the mouse genome, undergo two phases. The first phase is characterized by elevated deposition of LTRs and their utilization in reshaping gene regulatory networks. The second phase is characterized by rapid gene family expansion due to continuous accumulation of LINEs and it appears that, in some instances at least, this could become a runaway process. We provide an example in which this has happened and we present a simulation supporting the possibility of the runaway process. Altogether we provide evidence of the contribution of retrotransposons to the expansion and evolution of gene families. Our findings emphasize the putative importance of these elements in diversification and adaptation in the human and mouse lineages.
- Burton, B. K., Balwani, M., Feillet, F., Barić, I., Burrow, T. A., Camarena Grande, C., Coker, M., Consuelo-Sánchez, A., Deegan, P., Di Rocco, M., Enns, G. M., Erbe, R., Ezgu, F., Ficicioglu, C., Furuya, K. N., Kane, J., Laukaitis, C., Mengel, E., Neilan, E. G., , Nightingale, S., et al. (2015). A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency. The New England journal of medicine, 373(11), 1010-20.More infoLysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia.
- Laukaitis, C. M., Critser, E. S., & Karn, R. C. (1997). Salivary androgen-binding protein (ABP) mediates sexual isolation in Mus Musculus. Evolution, 51(16), 2000-2005.
- Romagnolo, D. F., Papoutsis, A. J., Laukaitis, C., & Selmin, O. I. (2015). Constitutive expression of AhR and BRCA-1 promoter CpG hypermethylation as biomarkers of ERα-negative breast tumorigenesis. BMC cancer, 15(1), 1026.More infoOnly 5-10 % of breast cancer cases is linked to germline mutations in the BRCA-1 gene and occurs early in life. Conversely, sporadic breast tumors, which represent 90-95 % of breast malignancies, have lower BRCA-1 expression, but not mutated BRCA-1 gene, and tend to occur later in life in combination with other genetic alterations and/or environmental exposures. The latter may include environmental and dietary factors that activate the aromatic hydrocarbon receptor (AhR). Therefore, understanding if changes in expression and/or activation of the AhR are associated with somatic inactivation of the BRCA-1 gene may provide clues for breast cancer therapy.
- Karn, R. C., & Laukaitis, C. M. (2014). Selection shaped the evolution of mouse androgen-binding protein (ABP) function and promoted the duplication of Abp genes. Biochemical Society transactions, 42(4), 851-60.More infoIn the present article, we summarize two aspects of our work on mouse ABP (androgen-binding protein): (i) the sexual selection function producing incipient reinforcement on the European house mouse hybrid zone, and (ii) the mechanism behind the dramatic expansion of the Abp gene region in the mouse genome. Selection unifies these two components, although the ways in which selection has acted differ. At the functional level, strong positive selection has acted on key sites on the surface of one face of the ABP dimer, possibly to influence binding to a receptor. A different kind of selection has apparently driven the recent and rapid expansion of the gene region, probably by increasing the amount of Abp transcript, in one or both of two ways. We have shown previously that groups of Abp genes behave as LCRs (low-copy repeats), duplicating as relatively large blocks of genes by NAHR (non-allelic homologous recombination). The second type of selection involves the close link between the accumulation of L1 elements and the expansion of the Abp gene family by NAHR. It is probably predicated on an initial selection for increased transcription of existing Abp genes and/or an increase in Abp gene number providing more transcriptional sites. Either or both could increase initial transcript production, a quantitative change similar to increasing the volume of a radio transmission. In closing, we also provide a note on Abp gene nomenclature.
- Karn, R. C., Chung, A. G., & Laukaitis, C. M. (2014). Did androgen-binding protein paralogs undergo neo- and/or Subfunctionalization as the Abp gene region expanded in the mouse genome?. PloS one, 9(12), e115454.More infoThe Androgen-binding protein (Abp) region of the mouse genome contains 30 Abpa genes encoding alpha subunits and 34 Abpbg genes encoding betagamma subunits, their products forming dimers composed of an alpha and a betagamma subunit. We endeavored to determine how many Abp genes are expressed as proteins in tears and saliva, and as transcripts in the exocrine glands producing them. Using standard PCR, we amplified Abp transcripts from cDNA libraries of C57BL/6 mice and found fifteen Abp gene transcripts in the lacrimal gland and five in the submandibular gland. Proteomic analyses identified proteins corresponding to eleven of the lacrimal gland transcripts, all of them different from the three salivary ABPs reported previously. Our qPCR results showed that five of the six transcripts that lacked corresponding proteins are expressed at very low levels compared to those transcripts with proteins. We found 1) no overlap in the repertoires of expressed Abp paralogs in lacrimal gland/tears and salivary glands/saliva; 2) substantial sex-limited expression of lacrimal gland/tear expressed-paralogs in males but no sex-limited expression in females; and 3) that the lacrimal gland/tear expressed-paralogs are found exclusively in ancestral clades 1, 2 and 3 of the five clades described previously while the salivary glands/saliva expressed-paralogs are found only in clade 5. The number of instances of extremely low levels of transcription without corresponding protein production in paralogs specific to tears and saliva suggested the role of subfunctionalization, a derived condition wherein genes that may have been expressed highly in both glands ancestrally were down-regulated subsequent to duplication. Thus, evidence for subfunctionalization can be seen in our data and we argue that the partitioning of paralog expression between lacrimal and salivary glands that we report here occurred as the result of adaptive evolution.
- Janoušek, V., Karn, R. C., & Laukaitis, C. M. (2013). The role of retrotransposons in gene family expansions: insights from the mouse Abp gene family. BMC evolutionary biology, 13, 107.More infoRetrotransposons have been suggested to provide a substrate for non-allelic homologous recombination (NAHR) and thereby promote gene family expansion. Their precise role, however, is controversial. Here we ask whether retrotransposons contributed to the recent expansions of the Androgen-binding protein (Abp) gene families that occurred independently in the mouse and rat genomes.
- Karn, R. C., Chung, A. G., & Laukaitis, C. M. (2013). Shared and unique proteins in human, mouse and rat saliva proteomes: Footprints of functional adaptation. Proteomes, 1(3), 275-289.More infoThe overall goal of our study was to compare the proteins found in the saliva proteomes of three mammals: human, mouse and rat. Our first objective was to compare two human proteomes with very different analysis depths. The 89 shared proteins in this comparison apparently represent a core of highly-expressed human salivary proteins. Of the proteins unique to each proteome, one-half to 2/3 lack signal peptides and probably are contaminants instead of less highly-represented salivary proteins. We recently published the first rodent saliva proteomes with salivas collected from the genome mouse (C57BL/6) and the genome rat (BN/SsNHsd/Mcwi). Our second objective was to compare the proteins in the human proteome with those we identified in the genome mouse and rat to determine those common to all three mammals as well as the specialized rodent subset. We also identified proteins unique to each of the three mammals because differences in the secreted protein constitutions can provide clues to differences in the evolutionary adaptation of the secretions in the three different mammals.
- Laukaitis, C., Nelson-Moseke, A. C., Jeter, J. M., Cui, H., Roe, D. J., Chambers, S. K., & Laukaitis, C. M. (2013). An unusual BRCA mutation distribution in a high risk cancer genetics clinic. Familial cancer, 12(1).More infoThe Database of Individuals at High Risk for Breast, Ovarian, or Other Hereditary Cancers at the Arizona Cancer Center in Tucson, Arizona assesses cancer risk factors and outcomes in patients with a family history of cancer or a known genetic mutation. We analyzed the subset of clinic probands who carry deleterious BRCA gene mutations to identify factors that could explain why mutations in BRCA2 outnumber those in BRCA1. Medical, family, social, ethnic and genetic mutation histories were collected from consenting patients' electronic medical records. Differences between BRCA1 and BRCA2 probands from this database were analyzed for statistical significance and compared to published analyses. A significantly higher proportion of our clinic probands carry mutations in BRCA2 than BRCA1, compared with previous reports of mutation prevalence. This also holds true for the Hispanic sub-group. Probands with BRCA2 mutations were significantly more likely than their BRCA1 counterparts to present to the high risk clinic without a diagnosis of cancer. Other differences between the groups were not significant. Six previously unreported BRCA2 mutations appear in our clinic population. The increased proportion of probands carrying deleterious BRCA2 mutations is likely multifactorial, but may reflect aspects of Southern Arizona's unique ethnic heritage.
- Laukaitis, C. M., Erdman, S. H., & Gerner, E. W. (2012). Chemoprevention in patients with genetic risk of colorectal cancers. Colorectal cancer, 1(3), 225-240.More infoA number of genetic syndromes are known to convey a high risk of colorectal cancer. Current standards of medical practice for these patients involve genetic testing followed by screening and surgical procedures. Pharmaceutical therapies for any of these syndromes are limited in number and are generally not approved by any regulatory body for applications in these genetic groups. This review discusses advances in mechanistic understanding of the disease processes leading to the development of promising pharmaceutical therapies. Clinical trials of potential chemotherapeutic agents must focus on the reduction of disease-related events, including cancer and cancer-related mortality, in patients with genetic syndromes.
- Laukaitis, C. M., Mauss, C., & Karn, R. C. (2012). Congenic strain analysis reveals genes that are rapidly evolving components of a prezygotic isolation mechanism mediating incipient reinforcement. PloS one, 7(4), e35898.More infoTwo decades ago, we developed a congenic strain of Mus musculus, called b-congenic, by replacing the androgen-binding protein Abpa27(a) allele in the C3H/HeJ genome with the Abpa27(b) allele from DBA/2J. We and other researchers used this b-congenic strain and its C3H counterpart, the a-congenic strain, to test the hypothesis that, given the choice between signals from two strains with different a27 alleles on the same genetic background, test subjects would prefer the homosubspecific one. It was our purpose in undertaking this study to characterize the segment transferred from DBA to the C3H background in producing the b-congenic strain on which a role for ABPA27 in behavior has been predicated. We determined the size of the chromosome 7 segment transferred from DBA and the genes it contains that might influence preference. We found that the "functional" DBA segment is about 1% the size of the mouse haploid genome and contains at least 29 genes expressed in salivary glands, however, only three of these encode proteins identified in the mouse salivary proteome. At least two of the three genes Abpa27, Abpbg26 and Abpbg27 encoding the subunits of androgen-binding protein ABP dimers evolved under positive selection and the third one may have also. In the sense that they are subunits of the same two functional entities, the ABP dimers, we propose that their evolutionary histories might not be independent of each other.
- Laukaitis, C., & Laukaitis, C. M. (2012). Genetics for the general internist. The American journal of medicine, 125(1).More infoThe internist's goal is to determine a patient's disease risk and to implement preventative interventions. Genetic evaluation is a powerful risk assessment tool, and new interventions target previously untreatable genetic disorders. The purpose of this review is to educate the general internist about common genetic conditions affecting adult patients, with special emphasis on diagnoses with an effective intervention, including hereditary cancer syndromes and cardiovascular disorders. Basic tenets of genetic counseling, complex genetic disease, and management of adults with genetic diagnoses also are discussed.
- Laukaitis, C., Karn, R. C., & Laukaitis, C. M. (2012). The roles of gene duplication, gene conversion and positive selection in rodent Esp and Mup pheromone gene families with comparison to the Abp family. PloS one, 7(10).More infoThree proteinaceous pheromone families, the androgen-binding proteins (ABPs), the exocrine-gland secreting peptides (ESPs) and the major urinary proteins (MUPs) are encoded by large gene families in the genomes of Mus musculus and Rattus norvegicus. We studied the evolutionary histories of the Mup and Esp genes and compared them with what is known about the Abp genes. Apparently gene conversion has played little if any role in the expansion of the mouse Class A and Class B Mup genes and pseudogenes, and the rat Mups. By contrast, we found evidence of extensive gene conversion in many Esp genes although not in all of them. Our studies of selection identified at least two amino acid sites in β-sheets as having evolved under positive selection in the mouse Class A and Class B MUPs and in rat MUPs. We show that selection may have acted on the ESPs by determining K(a)/K(s) for Exon 3 sequences with and without the converted sequence segment. While it appears that purifying selection acted on the ESP signal peptides, the secreted portions of the ESPs probably have undergone much more rapid evolution. When the inner gene converted fragment sequences were removed, eleven Esp paralogs were present in two or more pairs with K(a)/K(s) >1.0 and thus we propose that positive selection is detectable by this means in at least some mouse Esp paralogs. We compare and contrast the evolutionary histories of all three mouse pheromone gene families in light of their proposed functions in mouse communication.
- Bímová, B. V., Macholán, M., Baird, S. J., Munclinger, P., Dufková, P., Laukaitis, C. M., Karn, R. C., Luzynski, K., Tucker, P. K., & Piálek, J. (2011). Reinforcement selection acting on the European house mouse hybrid zone. Molecular ecology, 20(11), 2403-24.More infoBehavioural isolation may lead to complete speciation when partial postzygotic isolation acts in the presence of divergent-specific mate-recognition systems. These conditions exist where Mus musculus musculus and M. m. domesticus come into contact and hybridize. We studied two mate-recognition signal systems, based on urinary and salivary proteins, across a Central European portion of the mouse hybrid zone. Introgression of the genomic regions responsible for these signals: the major urinary proteins (MUPs) and androgen binding proteins (ABPs), respectively, was compared to introgression at loci assumed to be nearly neutral and those under selection against hybridization. The preference of individuals taken from across the zone regarding these signals was measured in Y mazes, and we develop a model for the analysis of the transition of such traits under reinforcement selection. The strongest assortative preferences were found in males for urine and females for ABP. Clinal analyses confirm nearly neutral introgression of an Abp locus and two loci closely linked to the Abp gene cluster, whereas two markers flanking the Mup gene region reveal unexpected introgression. Geographic change in the preference traits matches our reinforcement selection model significantly better than standard cline models. Our study confirms that behavioural barriers are important components of reproductive isolation between the house mouse subspecies.
- Laukaitis, C. M., & Gerner, E. W. (2011). DFMO: targeted risk reduction therapy for colorectal neoplasia. Best practice & research. Clinical gastroenterology, 25(4-5), 495-506.More infoStrategies to decrease intracellular polyamine levels have been studied for their efficacy in reducing colorectal cancer (CRC) risk. A successful strategy combined agents that decreased polyamine synthesis by inhibiting ornithine decarboxylase with difluoromethylornithine (DFMO), and increased cellular export of polyamines by activating the spermidine/spermine acetyl transferase with non-steroidal anti-inflammatory drugs (NSAIDs). A Phase III trial treating resected adenoma patients with DFMO plus sulindac demonstrated marked reduction of metachronous adenomas, advanced adenomas and multiple adenomas compared to placebo. This combination regimen was well-tolerated, however there was a non-significant excess of cardiovascular events in the treatment arm compared to placebo as well as modest ototoxicity. Targeting this therapy to people at elevated risk of CRC, and employing clinical and genetic predictors, should improve patient benefit and reduce the risk of side effects to improve the acceptability of this strategy.
- Laukaitis, C., Karn, R. C., & Laukaitis, C. M. (2011). Positive selection shaped the convergent evolution of independently expanded kallikrein subfamilies expressed in mouse and rat saliva proteomes. PloS one, 6(6).More infoWe performed proteomics studies of salivas from the genome mouse (C57BL/6 strain) and the genome rat (BN/SsNHsd/Mcwi strain). Our goal was to identify salivary proteins with one or more of three characteristics that may indicate that they have been involved in adaptation: 1) rapid expansion of their gene families; 2) footprints of positive selection; and/or 3) sex-limited expression. The results of our proteomics studies allow direct comparison of the proteins expressed and their levels between the sexes of the two rodent species. Twelve members of the Mus musculus species-specific kallikrein subfamily Klk1b showed sex-limited expression in the mouse saliva proteomes. By contrast, we did not find any of the Rattus norvegicus species-specific kallikrein subfamily Klk1c proteins in male or female genome rat, nor transcripts in their submandibular glands. On the other hand, we detected expression of this family as transcripts in the submandibular glands of both sexes of Sprague-Dawley rats. Using the CODEML program in the PAML package, we demonstrate that the two rodent kallikrein subfamilies have apparently evolved rapidly under the influence of positive selection that continually remodeled the amino acid sites on the same face in the members of the subfamilies. Thus, although their kallikrein subfamily expansions were independent, this evolutionary pattern has occurred in parallel in the two rodent species, suggesting a form of convergent evolution at the molecular level. On the basis of this new data, we suggest that the previous speculative function of the species-specific rodent kallikreins as important solely in wound healing in males be investigated further. In addition to or instead of that function, we propose that their sex-limited expression, coupled with their rapid evolution may be clues to an as-yet-undetermined interaction between the sexes.
- Zhou, X., Wei, Y., Xie, F., Laukaitis, C. M., Karn, R. C., Kluetzman, K., Gu, J., Zhang, Q., Roberts, D. W., & Ding, X. (2011). A novel defensive mechanism against acetaminophen toxicity in the mouse lateral nasal gland: role of CYP2A5-mediated regulation of testosterone homeostasis and salivary androgen-binding protein expression. Molecular pharmacology, 79(4), 710-23.More infoTo identify novel factors or mechanisms that are important for the resistance of tissues to chemical toxicity, we have determined the mechanisms underlying the previously observed increases in resistance to acetaminophen (APAP) toxicity in the lateral nasal gland (LNG) of the male Cyp2g1-null/Cyp2a5-low mouse. Initial studies established that Cyp2a5-null mice, but not a newly generated strain of Cyp2g1-null mice, were resistant to APAP toxicity in the LNG; therefore, subsequent studies were focused on the Cyp2a5-null mice. Compared with the wild-type (WT) male mouse, the Cyp2a5-null male mouse had intact capability to metabolize APAP to reactive intermediates in the LNG, as well as unaltered circulating levels of APAP, APAP-GSH, APAP-glucuronide, and APAP-sulfate. However, it displayed reduced tissue levels of APAP and APAP-GSH and increased tissue levels of testosterone and salivary androgen-binding protein (ABP) in the LNG. Furthermore, we found that ABP was able to compete with GSH and cellular proteins for adduction with reactive metabolites of APAP in vitro. The amounts of APAP-ABP adducts formed in vivo were greater, whereas the amounts of APAP adducts formed with other cellular proteins were substantially lower, in the LNG of APAP-treated male Cyp2a5-null mice compared with the LNG of APAP-treated male WT mice. We propose that through its critical role in testosterone metabolism, CYP2A5 regulates 1) the bioavailability of APAP and APAP-GSH (presumably through modulation of the rates of xenobiotic excretion from the LNG) and 2) the expression of ABP, which can quench reactive APAP metabolites and thereby spare critical cellular proteins from inactivation.
- Laukaitis, C., Karn, R. C., Young, J. M., & Laukaitis, C. M. (2010). A candidate subspecies discrimination system involving a vomeronasal receptor gene with different alleles fixed in M. m. domesticus and M. m. musculus. PloS one, 5(9).More infoAssortative mating, a potentially efficient prezygotic reproductive barrier, may prevent loss of genetic potential by avoiding the production of unfit hybrids (i.e., because of hybrid infertility or hybrid breakdown) that occur at regions of secondary contact between incipient species. In the case of the mouse hybrid zone, where two subspecies of Mus musculus (M. m. domesticus and M. m. musculus) meet and exchange genes to a limited extent, assortative mating requires a means of subspecies recognition. We based the work reported here on the hypothesis that, if there is a pheromone sufficiently diverged between M. m. domesticus and M. m. musculus to mediate subspecies recognition, then that process must also require a specific receptor(s), also sufficiently diverged between the subspecies, to receive the signal and elicit an assortative mating response. We studied the mouse V1R genes, which encode a large family of receptors in the vomeronasal organ (VNO), by screening Perlegen SNP data and identified one, Vmn1r67, with 24 fixed SNP differences most of which (15/24) are nonsynonymous nucleotide substitutions between M. m. domesticus and M. m. musculus. We observed substantial linkage disequilibrium (LD) between Vmn1r67 and Abpa27, a mouse salivary androgen-binding protein gene that encodes a proteinaceous pheromone (ABP) capable of mediating assortative mating, perhaps in conjunction with its bound small lipophilic ligand. The LD we observed is likely a case of association rather than residual physical linkage from a very recent selective sweep, because an intervening gene, Vmn1r71, shows significant intra(sub)specific polymorphism but no inter(sub)specific divergence in its nucleotide sequence. We discuss alternative explanations of these observations, for example that Abpa27 and Vmn1r67 are coevolving as signal and receptor to reinforce subspecies hybridization barriers or that the unusually divergent Vmn1r67 allele was not a product of fast positive selection, but was derived from an introgressed allele, possibly from Mus spretus.
- Laukaitis, C., Karn, R. C., & Laukaitis, C. M. (2009). The mechanism of expansion and the volatility it created in three pheromone gene clusters in the mouse (Mus musculus) genome. Genome biology and evolution, 1.More infoThree families of proteinaceous pheromones have been described in the house mouse: androgen-binding proteins (ABPs), exocrine gland-secreting peptides (ESPs), and major urinary proteins (MUPs), each of which is thought to communicate different information. All three are encoded by large gene clusters in different regions of the mouse genome, clusters that have expanded dramatically during mouse evolutionary history. We report copy number variation among the most recently duplicated Abp genes, which suggests substantial volatility in this gene region. It appears that groups of these genes behave as low copy repeats (LCRs), duplicating as relatively large blocks of genes by nonallelic homologous recombination. An analysis of gene conversion suggested that it did not contribute to the very low or absent divergence among the paralogs duplicated in this way. We evaluated the ESP and MUP gene regions for signs of the LCR pattern but could find no compelling evidence for duplication of gene blocks of any significant size. Assessment of the entire Abp gene region with the Mouse Paralogy Browser supported the conclusion that substantial volatility has occurred there. This was especially evident when comparing strains with all or part of the Mus musculus musculus or Mus musculus castaneus Abp region. No particularly remarkable volatility was observed in the other two gene families, and we discuss the significance of this in light of the various roles proposed for the three families of mouse proteinaceous pheromones.
- Laukaitis, C. M., Heger, A., Blakley, T. D., Munclinger, P., Ponting, C. P., & Karn, R. C. (2008). Rapid bursts of androgen-binding protein (Abp) gene duplication occurred independently in diverse mammals. BMC evolutionary biology, 8, 46.More infoThe draft mouse (Mus musculus) genome sequence revealed an unexpected proliferation of gene duplicates encoding a family of secretoglobin proteins including the androgen-binding protein (ABP) alpha, beta and gamma subunits. Further investigation of 14 alpha-like (Abpa) and 13 beta- or gamma-like (Abpbg) undisrupted gene sequences revealed a rich diversity of developmental stage-, sex- and tissue-specific expression. Despite these studies, our understanding of the evolution of this gene family remains incomplete. Questions arise from imperfections in the initial mouse genome assembly and a dearth of information about the gene family structure in other rodents and mammals.
- Laukaitis, C. M., & Karn, R. C. (2005). Evolution of the secretoglobins: A genomic and proteomic view. Biological Journal of the Linnean Society, 84, 493-501.
- Laukaitis, C. M., Dlouhy, S. R., Emes, R. D., Ponting, C. P., & Karn, R. C. (2005). Diverse spatial, temporal, and sexual expression of recently duplicated androgen-binding protein genes in Mus musculus. BMC evolutionary biology, 5, 40.More infoThe genes for salivary androgen-binding protein (ABP) subunits have been evolving rapidly in ancestors of the house mouse Mus musculus, as evidenced both by recent and extensive gene duplication and by high ratios of nonsynonymous to synonymous nucleotide substitution rates. This makes ABP an appropriate model system with which to investigate how recent adaptive evolution of paralogous genes results in functional innovation (neofunctionalization).
- Emes, R. D., Riley, M. C., Laukaitis, C. M., Goodstadt, L., Karn, R. C., & Ponting, C. P. (2004). Comparative evolutionary genomics of androgen-binding protein genes. Genome research, 14(8), 1516-29.More infoAllelic variation within the mouse androgen-binding protein (ABP) alpha subunit gene (Abpa) has been suggested to promote assortative mating and thus prezygotic isolation. This is consistent with the elevated evolutionary rates observed for the Abpa gene, and the Abpb and Abpg genes whose products (ABPbeta and ABPgamma) form heterodimers with ABPalpha. We have investigated the mouse sequence that contains the three Abpa/b/g genes, and orthologous regions in rat, human, and chimpanzee genomes. Our studies reveal extensive "remodeling" of this region: Duplication rates of Abpa-like and Abpbg-like genes in mouse are >2 orders of magnitude higher than the average rate for all mouse genes; synonymous nucleotide substitution rates are twofold higher; and the Abpabg genomic region has expanded nearly threefold since divergence of the rodents. During this time, one in six amino acid sites in ABPbetagamma-like proteins appear to have been subject to positive selection; these may constitute a site of interaction with receptors or ligands. Greater adaptive variation among Abpbg-like sequences than among Abpa-like sequences suggests that assortative mating preferences are more influenced by variation in Abpbg-like genes. We propose a role for ABPalpha/beta/gamma proteins as pheromones, or in modulating odorant detection. This would account for the extraordinary adaptive evolution of these genes, and surrounding genomic regions, in murid rodents.
- Karn, R. C., & Laukaitis, C. M. (2003). Characterization of two forms of mouse salivary androgen-binding protein (ABP): implications for evolutionary relationships and ligand-binding function. Biochemistry, 42(23), 7162-70.More infoMouse salivary androgen-binding protein (ABP) is a member of the secretoglobin family produced in the submaxillary glands of house mice (Mus musculus). We report the cDNA sequences and amino acid sequences of the beta and gamma subunits of ABP from a mouse cDNA library, identifying the two subunits by their pIs and molecular weights. An anomalously high molecular weight of the alpha subunit is likely due to glycosylation at a single site. A phylogenetic comparison of the three subunits of ABP with the chains of other mammalian secretoglobins shows that ABP is most closely related to mouse lachrymal protein and to the major cat allergen Fel dI. An evaluation of the most conserved residues in ABP and the other secretoglobins, in light of structural data reported by others [Callebaut, I., Poupon, A., Bally, R., Demaret, J.-P., Housset, D., Delettre, J., Hossenlopp, P., and Mornon, J.-P. (2000) Ann. N.Y. Acad. Sci. 923, 90-112; Pattabiraman, N., Matthews, J., Ward, K., Mantile-Selvaggi, G., Miele, L., and Mukherjee, A. (2000) Ann. N.Y. Acad. Sci. 923, 113-127], allows us to draw conclusions about the critical residues important in ligand binding by the two different ABP dimers and to assess the importance of ligand binding in the function of the molecule. In addition to the cDNAs, which represent those of the musculus subspecies of Mus musculus, we also report the coding regions of the beta and gamma subunit cDNAs from two other mouse inbred strains which represent the other two subspecies: M. musculus domesticus and M. musculus castaneus. The high nonsynonymous/synonymous substitution rate ratios (K(a)/K(s)) for both the beta and gamma subunits suggest that these two proteins are evolving under strong directional selection, as has been reported for the alpha subunit [Hwang, J., Hofstetter, J., Bonhomme, F., and Karn, R. (1997) J. Hered. 88, 93-97; Karn, R., and Clements, M. (1999) Biochem. Genet. 37, 187-199].
- Laukaitis, C. M., Dlouhy, S. R., & Karn, R. C. (2003). The mouse salivary androgen-binding protein (ABP) gene cluster on chromosomes 7: characterization and evolutionary relationships. Mammalian genome : official journal of the International Mammalian Genome Society, 14(10), 679-91.More infoMouse salivary androgen-binding protein (ABP) is a pair of dimers, composed of an alpha subunit disulfide bridged to either a beta or a gamma subunit. It has been proposed that each subunit is encoded by a distinct gene: Abpa, Abpb, and Abpg for the alpha, beta, and gamma subunits, respectively. We report here the structures and sequences of the genes that encode these three subunits. Each gene has three exons separated by two introns. Mouse salivary ABP is a member of the secretoglobin family, and we compare the structure of the three ABP subunit genes to those of 18 other mammalian secretoglobins. We map the three genes as a gene cluster located 10 cM from the centromere of Chromosome (Chr) 7 and show that Abpa is the closest of the three to the gene for glucose phosphate isomerase (GPI) and that Abpg is the closest to the centromere, with Abpb mapping between them. Abpa is oriented in the opposite direction to Abpb and Abpg, with its 5' end directed toward their 5' ends. We compare the location of these genes with other secretoglobin genes in the mouse genome and with the known locations of secretoglobin genes in the human genome and present evidence that strong positive selection has driven the divergence of the coding regions of Abpb and Abpg since the putative duplication event that created them.
- Laukaitis, C. M., Webb, D. J., Donais, K., & Horwitz, A. F. (2001). Differential dynamics of alpha 5 integrin, paxillin, and alpha-actinin during formation and disassembly of adhesions in migrating cells. The Journal of cell biology, 153(7), 1427-40.More infoTo investigate the mechanisms by which adhesions form and disperse in migrating cells, we expressed alpha 5 integrin, alpha-actinin, and paxillin as green fluorescent protein (GFP) fusions. All localized with their endogenous counterparts and did not perturb migration when expressed at moderate levels. alpha 5-GFP also rescued the adhesive defects in CHO B2 cells, which are alpha 5 integrin deficient. In ruffling cells, alpha 5-GFP and alpha-actinin--GFP localized prominently at the leading edge in membrane protrusions. Of the three GFP fusion proteins that we examined, paxillin was the first component to appear visibly organized in protrusive regions of the cell. When a new protrusion formed, the paxillin appeared to remodel from older to newer adhesions at the leading edge. alpha-Actinin subsequently entered adhesions, which translocated toward the cell center, and inhibited paxillin turnover. The new adhesions formed from small foci of alpha-actinin--GFP and paxillin-GFP, which grew in size. Subsequently, alpha 5 integrin entered the adhesions to form visible complexes, which served to stabilize the adhesions. alpha 5-GFP also resided in endocytic vesicles that emanated from the leading edge of protrusions. Integrin vesicles at the cell rear moved toward the cell body. As cells migrated, alpha 5 vesicles also moved from a perinuclear region to the base of the lamellipodium. The alpha 5 vesicles colocalized with transferrin receptor and FM 4-64 dye. After adhesions broke down in the rear, alpha 5-GFP was found in fibrous structures behind the cell, whereas alpha-actinin--GFP and paxillin-GFP moved up the lateral edge of retracting cells as organized structures and then dissipated.
- Talley, H. M., Laukaitis, C. M., & Karn, R. C. (2001). Female preference for male saliva: implications for sexual isolation of Mus musculus subspecies. Evolution; international journal of organic evolution, 55(3), 631-4.More infoWe studied the effects of a single genetic change on a complex mammalian behavior using animals congenic for two variants of Abpa, the gene for the alpha subunit of mouse salivary androgen-binding protein (ABP), in two-way preference tests. Females exhibited a preference for investigating salivas of males of their own genetic type of ABP but not for urines of either type of male. This preference behavior is consistent for samples of mice from geographically diverse populations of Mus musculus domesticus and M. m. musculus. These findings provide an explanation for the observation that this gene is evolving under strong selection.
- Knight, B., Laukaitis, C., Akhtar, N., Hotchin, N. A., Edlund, M., & Horwitz, A. R. (2000). Visualizing muscle cell migration in situ. Current biology : CB, 10(10), 576-85.More infoCell migration has been studied extensively by manipulating and observing cells bathed in putative chemotactic or chemokinetic agents on planar substrates. This environment differs from that in vivo and, consequently, the cells can behave abnormally. Embryo slices provide an optically accessible system for studying cellular navigation pathways during development. We extended this system to observe the migration of muscle precursors from the somite into the forelimb, their cellular morphology, and the localization of green fluorescent protein (GFP)-tagged adhesion-related molecules under normal and perturbed conditions.
- Huynh, J. M., & Laukaitis, C. M. (2016. Panel testing reveals nonsense and missense CDH1 mutations in families without Hereditary Diffuse Gastric Cancer(pp 232-236).